Dual electrode system for a continuous analyte sensor

ABSTRACT

Disclosed herein are systems and methods for a continuous analyte sensor, such as a continuous glucose sensor. One such system utilizes first and second working electrodes to measure additional analyte or non-analyte related signal. Such measurements may provide a background and/or sensitivity measurement(s) for use in processing sensor data and may be used to trigger events such as digital filtering of data or suspending display of data.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 15/419,977, filed Jan. 30, 2017, which is a continuation of U.S.application Ser. No. 12/748,024, filed Mar. 26, 2010, now U.S. Pat. No.9,579,053, which is a continuation of U.S. application Ser. No.12/335,403, filed Dec. 15, 2008, now U.S. Pat. No. 8,911,369, which is acontinuation of U.S. application Ser. No. 11/543,539, filed Oct. 4,2006, now U.S. Pat. No. 7,467,003, which is a continuation-in-part ofU.S. application Ser. No. 11/004,561, filed Dec. 3, 2004, now U.S. Pat.No. 7,715,893, which claims the benefit of U.S. Provisional ApplicationNo. 60/527,323, filed Dec. 5, 2003, U.S. Provisional Application No.60/587,787, filed Jul. 13, 2004, and U.S. Provisional Application No.60/614,683, filed Sep. 30, 2004. Each of the aforementioned applicationsis incorporated by reference herein in its entirety, and each is herebyexpressly made a part of this specification.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods formeasuring an analyte concentration in a host.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which may cause anarray of physiological derangements (for example, kidney failure, skinulcers, or bleeding into the vitreous of the eye) associated with thedeterioration of small blood vessels. A hypoglycemic reaction (low bloodsugar) may be induced by an inadvertent overdose of insulin, or after anormal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a diabetic person carries a self-monitoring bloodglucose (SMBG) monitor, which typically comprises uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a diabeticwill normally only measure his or her glucose level two to four timesper day. Unfortunately, these time intervals are so far spread apartthat the diabetic will likely find out too late, sometimes incurringdangerous side effects, of a hyper- or hypo-glycemic condition. In fact,it is not only unlikely that a diabetic will take a timely SMBG value,but the diabetic will not know if their blood glucose value is going up(higher) or down (lower) based on conventional methods, inhibiting theirability to make educated insulin therapy decisions.

SUMMARY OF THE INVENTION

A variety of continuous glucose sensors have been developed fordetecting and/or quantifying glucose concentration in a host. Thesesensors have typically required one or more blood glucose measurements,or the like, from which to calibrate the continuous glucose sensor tocalculate the relationship between the current output of the sensor andblood glucose measurements, to provide meaningful values to a patient ordoctor. Unfortunately, continuous glucose sensors are conventionallyalso sensitive to non-glucose related changes in the baseline currentand sensitivity over time, for example, due to changes in a host'smetabolism, maturation of the tissue at the biointerface of the sensor,interfering species which cause a measurable increase or decrease in thesignal, or the like. Therefore, in addition to initial calibration,continuous glucose sensors should be responsive to baseline and/orsensitivity changes over time, which requires recalibration of thesensor. Consequently, users of continuous glucose sensors have typicallybeen required to obtain numerous blood glucose measurements daily and/orweekly in order to maintain calibration of the sensor over time.

The preferred embodiments provide improved calibration techniques thatutilize electrode systems and signal processing that providesmeasurements useful in simplifying and updating calibration that allowsthe patient increased convenience (for example, by requiring fewerreference glucose values) and confidence (for example, by increasingaccuracy of the device).

One aspect of the preferred embodiments is a method for measuring asensitivity change of a glucose sensor implanted in a host over a timeperiod comprising: 1) measuring a first signal in the host by obtainingat least one glucose-related sensor data point, wherein the first signalis measured at a glucose-measuring electrode disposed beneath anenzymatic portion of a membrane system on the sensor; 2) measuring asecond signal in the host by obtaining at least one non-glucose constantdata point, wherein the second signal is measured beneath the inactiveor non-enzymatic portion of the membrane system on the sensor; and 3)monitoring the second signal over a time period, whereby a sensitivitychange associated with solute transport through the membrane system ismeasured. In one embodiment, the second signal is indicative of apresence or absence of a water-soluble analyte. The water-solubleanalyte may comprise urea. In one embodiment, the second signal ismeasured at an oxygen-measuring electrode disposed beneath anon-enzymatic portion of the membrane system. In one embodiment, theglucose-measuring electrode incrementally measures oxygen, whereby thesecond signal is measured. In one embodiment, the second signal ismeasured at an oxygen sensor disposed beneath the membrane system. Inone embodiment, the sensitivity change is calculated as aglucose-to-oxygen ratio, whereby an oxygen threshold is determined thatis indicative of a stability of the glucose sensor. One embodimentfurther comprises filtering the first signal responsive to the stabilityof the glucose sensor. One embodiment further comprises displaying aglucose value derived from the first signal, wherein the display issuspended depending on the stability of the glucose sensor. Oneembodiment further comprises calibrating the first signal, wherein thecalibrating step is suspended when the glucose sensor is determined tobe stable. One embodiment further comprises calibrating the glucosesensor when the sensitivity change exceeds a preselected value. The stepof calibrating may comprise receiving a reference signal from areference analyte monitor, the reference signal comprising at least onereference data point. The step of calibrating may comprise using thesensitivity change to calibrate the glucose sensor. The step ofcalibrating may be performed repeatedly at a frequency responsive to thesensitivity change. One embodiment further comprises determining astability of glucose transport through the membrane system, wherein thestability of glucose transport is determined by measuring thesensitivity change over a time period. One embodiment further comprisesa step of prohibiting calibration of the glucose sensor when glucosetransport is determined to be unstable. One embodiment further comprisesa step of filtering at least one glucose-related sensor data point whenglucose transport is determined to be unstable.

Another aspect of the preferred embodiments is a system for measuringglucose in a host, comprising a glucose-measuring electrode configuredto generate a first signal comprising at least one glucose-relatedsensor data point, wherein the glucose-measuring electrode is disposedbeneath an enzymatic portion of a membrane system on a glucose sensorand a transport-measuring electrode configured to generate a secondsignal comprising at least one non-glucose constant analyte data point,wherein the transport-measuring electrode is situated beneath themembrane system on the glucose sensor. One embodiment further comprisesa processor module configured to monitor the second signal whereby asensitivity change associated with transport of the non-glucose constantanalyte through the membrane system over a time period is measured. Inone embodiment, the transport-measuring electrode is configured tomeasure oxygen. In one embodiment, the processor module is configured todetermine whether a glucose-to-oxygen ratio exceeds a threshold level,wherein a value is calculated from the first signal and the secondsignal, wherein the value is indicative of the glucose-to-oxygen ratio.In one embodiment, the processor module is configured to calibrate theglucose-related sensor data point in response to the sensitivity change.In one embodiment, the processor module is configured to receivereference data from a reference analyte monitor, the reference datacomprising at least one reference data point, wherein the processormodule is configured to use the reference data point for calibrating theglucose-related sensor data point. In one embodiment, the processormodule is configured to use the sensitivity change for calibrating theglucose-related sensor data point. In one embodiment, the processormodule is configured to calibrate the glucose-related sensor data pointrepeatedly at a frequency, wherein the frequency is selected based onthe sensitivity change. One embodiment further comprises a stabilitymodule configured to determine a stability of glucose transport throughthe membrane system, wherein the stability of glucose transport iscorrelated with the sensitivity change. In one embodiment, the processormodule is configured to prohibit calibration of the glucose-relatedsensor data point when the stability of glucose transport falls below athreshold. In one embodiment, the processor module is configured toinitiate filtering of the glucose-related sensor data point when thestability of glucose transport falls below a threshold.

Another aspect of the preferred embodiments is a method for processingdata from a glucose sensor in a host, comprising: 1) measuring a firstsignal associated with glucose and non-glucose related electroactivecompounds, wherein the first signal is measured at a first electrodedisposed beneath an active enzymatic portion of a membrane system; 2)measuring a second signal associated with a non-glucose relatedelectroactive compound, wherein the second signal is measured at asecond electrode that is disposed beneath a non-enzymatic portion of themembrane system; and 3) monitoring the second signal over a time period,whereby a change in the non-glucose related electroactive compound inthe host is measured. One embodiment further comprises a step ofsubtracting the second signal from the first signal, whereby adifferential signal comprising at least one glucose sensor data point isdetermined. The step of subtracting may be performed electronically inthe sensor. Alternatively, the step of subtracting may be performeddigitally in the sensor or an associated receiver. One embodimentfurther comprises calibrating the glucose sensor, wherein the step ofcalibrating comprises: 1) receiving reference data from a referenceanalyte monitor, the reference data comprising at least two referencedata points; 2) providing at least two matched data pairs by matchingthe reference data to substantially time corresponding sensor data; and3) calibrating the glucose sensor using the two or more matched datapairs and the differential signal. One embodiment further comprises astep of calibrating the glucose sensor in response to a change in thenon-glucose related electroactive compound over the time period. Thestep of calibrating may comprise receiving reference data from areference analyte monitor, the reference data comprising at least onereference data point. The step of calibrating may comprise using thechange in the non-glucose related electroactive compound over the timeperiod to calibrate the glucose sensor. The step of calibrating may beperformed repeatedly at a frequency, wherein the frequency is selectedbased on the change in the non-glucose related electroactive compoundover the time period. One embodiment further comprises prohibitingcalibration of the glucose sensor when the change in the non-glucoserelated electroactive compound rises above a threshold during the timeperiod. One embodiment further comprises filtering the glucose sensordata point when the change in the non-glucose related electroactivecompound rises above a threshold during the time period. One embodimentfurther comprises measuring a third signal in the host by obtaining atleast one non-glucose constant data point, wherein the third signal ismeasured beneath the membrane system. One embodiment further comprisesmonitoring the third signal over a time period, whereby a sensitivitychange associated with solute transport through the membrane system ismeasured. In one embodiment, an oxygen-measuring electrode disposedbeneath the non-enzymatic portion of the membrane system measures thethird signal. In one embodiment, the first electrode measures the thirdsignal by incrementally measuring oxygen. In one embodiment, an oxygensensor disposed beneath the membrane system measures the third signal.One embodiment further comprises determining whether a glucose-to-oxygenratio exceeds a threshold level by calculating a value from the firstsignal and the second signal, wherein the value is indicative of theglucose-to-oxygen ratio. One embodiment further comprises calibratingthe glucose sensor in response to the sensitivity change measured over atime period. The step of calibrating may comprise receiving referencedata from a reference analyte monitor, the reference data comprising atleast one reference data point. The step of calibrating may compriseusing the sensitivity change. The step of calibrating may be performedrepeatedly at a frequency, wherein the frequency is selected based onthe sensitivity change. One embodiment further comprises determining aglucose transport stability through the membrane system, wherein theglucose transport stability corresponds to the sensitivity change over aperiod of time. One embodiment further comprises prohibiting calibrationof the glucose sensor when the glucose transport stability falls below athreshold. One embodiment further comprises filtering theglucose-related sensor data point when the glucose transport stabilityfalls below a threshold.

Still another aspect of the preferred embodiments is a system formeasuring glucose in a host, comprising a first working electrodeconfigured to generate a first signal associated with a glucose relatedelectroactive compound and a non-glucose related electroactive compound,wherein the first electrode is disposed beneath an active enzymaticportion of a membrane system on a glucose sensor; a second workingelectrode configured to generate a second signal associated with thenon-glucose related electroactive compound, wherein the second electrodeis disposed beneath a non-enzymatic portion of the membrane system onthe glucose sensor; and a processor module configured to monitor thesecond signal over a time period, whereby a change in the non-glucoserelated electroactive compound is measured. One embodiment furthercomprises a subtraction module configured to subtract the second signalfrom the first signal, whereby a differential signal comprising at leastone glucose sensor data point is determined. The subtraction module maycomprise a differential amplifier configured to electronically subtractthe second signal from the first signal. The subtraction module maycomprise at least one of hardware and software configured to digitallysubtract the second signal from the first signal. One embodiment furthercomprises a reference electrode, wherein the first working electrode andthe second working electrode are operatively associated with thereference electrode. One embodiment further comprises a counterelectrode, wherein the first working electrode and the second workingelectrode are operatively associated with the counter electrode. Oneembodiment further comprises a first reference electrode and a secondreference electrode, wherein the first reference electrode isoperatively associated with the first working electrode, and wherein thesecond reference electrode is operatively associated with the secondworking electrode. One embodiment further comprises a first counterelectrode and a second counter electrode, wherein the first counterelectrode is operatively associated with the first working electrode,and wherein the second counter electrode is operatively associated withthe second working electrode. One embodiment further comprises areference input module adapted to obtain reference data from a referenceanalyte monitor, the reference data comprising at least one referencedata point, wherein the processor module is configured to format atleast one matched data pair by matching the reference data tosubstantially time corresponding glucose sensor data and subsequentlycalibrating the system using at least two matched data pairs and thedifferential signal. In one embodiment, the processor module isconfigured to calibrate the system in response to the change in thenon-glucose related electroactive compound in the host over the timeperiod. In one embodiment, the processor module is configured to requestreference data from a reference analyte monitor, the reference datacomprising at least one reference data point, wherein the processormodule is configured to recalibrate the system using the reference data.In one embodiment, the processor module is configured to recalibrate thesystem using the change in the non-glucose related electroactivecompound measured over the time period. In one embodiment, the processormodule is configured to repeatedly recalibrate at a frequency, whereinthe frequency is selected based on the change in the non-glucose relatedelectroactive compound over the time period. In one embodiment, theprocessor module is configured to prohibit calibration of the systemwhen a change in the non-glucose related electroactive compound risesabove a threshold during the time period. In one embodiment, theprocessor module is configured to filter the glucose sensor data pointwhen the change in the non-glucose related electroactive compound risesabove a threshold during the time period. One embodiment furthercomprises a third electrode configured to generate a third signal, thethird signal comprising at least one non-glucose constant analyte datapoint, wherein the third electrode is disposed beneath the membranesystem on the sensor. The third electrode may be configured to measureoxygen. In one embodiment, the processor module is configured todetermine whether a glucose-to-oxygen ratio exceeds a threshold level,wherein a value indicative of the glucose-to-oxygen ratio is calculatedfrom the first signal and the second signal. In one embodiment, theprocessor module is configured to monitor the third signal over a timeperiod, whereby a sensitivity change associated with solute transportthrough the membrane system is measured. In one embodiment, theprocessor module is configured to calibrate the glucose-related sensordata point in response to the sensitivity change. In one embodiment, theprocessor module is configured to receive reference data from areference analyte monitor, the reference data comprising at least onereference data point, wherein the processor module is configured tocalibrate the glucose sensor data point using the reference data point.In one embodiment, the processor module is configured to calibrate theglucose-related sensor data point repeatedly at a frequency, wherein thefrequency is selected based on the sensitivity change. One embodimentfurther comprises a stability module configured to determine a stabilityof glucose transport through the membrane system, wherein the stabilityof glucose transport is correlated with the sensitivity change. In oneembodiment, the processor module is configured to prohibit calibrationof the glucose-related sensor data point when the stability of glucosetransport falls below a threshold. In one embodiment, the processormodule is configured to filter the glucose-related sensor data pointwhen the stability of glucose transport falls below a threshold.

In a first aspect, an analyte sensor configured for insertion into ahost for measuring an analyte in the host is provided the sensorcomprising a first working electrode disposed beneath an activeenzymatic portion of a sensor membrane; and a second working electrodedisposed beneath an inactive-enzymatic or a non-enzymatic portion of asensor membrane, wherein the first working electrode and the secondworking electrode each integrally form at least a portion of the sensor.

In an embodiment of the first aspect, the first working electrode andthe second working electrode are coaxial.

In an embodiment of the first aspect, at least one of the first workingelectrode and the second working electrode is twisted or helically woundto integrally form at least a portion of the sensor.

In an embodiment of the first aspect, the first working electrode andthe second working electrode are twisted together to integrally form anin vivo portion of the sensor.

In an embodiment of the first aspect, one of the first working electrodeand the second working electrode is deposited or plated over the otherof the first working electrode and the second working electrode.

In an embodiment of the first aspect, the first working electrode andthe second working electrode each comprise a first end and a second end,wherein the first ends are configured for insertion in the host, andwherein the second ends are configured for electrical connection tosensor electronics.

In an embodiment of the first aspect, the second ends are coaxial.

In an embodiment of the first aspect, the second ends are stepped.

In an embodiment of the first aspect, wherein the sensor furthercomprises at least one additional electrode selected from the groupconsisting of a reference electrode and a counter electrode.

In an embodiment of the first aspect, the additional electrode, togetherwith the first working electrode and the second working electrode,integrally form at least a portion of the sensor.

In an embodiment of the first aspect, the additional electrode islocated at a position remote from the first and second workingelectrodes.

In an embodiment of the first aspect, a surface area of the additionalelectrode is at least six times a surface area of at least one of thefirst working electrode and the second working electrode.

In an embodiment of the first aspect, the sensor is configured forimplantation into the host.

In an embodiment of the first aspect, the sensor is configured forsubcutaneous implantation in a tissue of a host.

In an embodiment of the first aspect, the sensor is configured forindwelling in a blood stream of a host.

In an embodiment of the first aspect, the sensor substantiallycontinuously measures an analyte concentration in a host.

In an embodiment of the first aspect, the sensor comprises a glucosesensor, and wherein the first working electrode is configured togenerate a first signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential.

In an embodiment of the first aspect, the second working electrode isconfigured to generate a second signal associated with noise of theglucose sensor, the noise comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential.

In an embodiment of the first aspect, the non-glucose relatedelectroactive species comprises at least one species selected from thegroup consisting of interfering species, non-reaction-related hydrogenperoxide, and other electroactive species.

In an embodiment of the first aspect, the sensor further compriseselectronics operably connected to the first working electrode and thesecond working electrode, and configured to provide the first signal andthe second signal to generate glucose concentration data substantiallywithout signal contribution due to non-glucose-related noise.

In an embodiment of the first aspect, the sensor further comprises anon-conductive material positioned between the first working electrodeand the second working electrode.

In an embodiment of the first aspect, each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured to provide at least two functions selected from the groupconsisting of electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In an embodiment of the first aspect, the sensor comprises a diffusionbarrier configured to substantially block diffusion of at least one ofan analyte and a co-analyte between the first working electrode and thesecond working electrode.

In a second aspect, a glucose sensor configured for insertion into ahost for measuring a glucose concentration in the host is provided, thesensor comprising a first working electrode configured to generate afirst signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential; and a secondworking electrode configured to generate a second signal associated withnoise of the glucose sensor comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential, whereinthe first working electrode and the second working electrode eachintegrally form at least a portion of the sensor.

In an embodiment of the second aspect, the first working electrode andthe second working electrode integrally form a substantial portion ofthe sensor configured for insertion in the host.

In an embodiment of the second aspect, the sensor further comprises areference electrode, wherein the first working electrode, the secondworking electrode, and the reference electrode each integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the second aspect, the sensor further comprises aninsulator, wherein the first working electrode, the second workingelectrode, and the insulator each integrally form a substantial portionof the sensor configured for insertion in the host.

In a third aspect, a system configured for measuring a glucoseconcentration in a host is provided, the system comprising a processormodule configured to receive or process a first signal associated withglucose and non-glucose related electroactive compounds, the glucose andnon-glucose related electroactive compounds having a first oxidationpotential, and to receive or process a second signal associated withnoise of the glucose sensor comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential, whereinthe first working electrode and the second working electrode eachintegrally form at least a portion of the sensor, and wherein theprocessor module is further configured to process the first signal andthe second signal to generate glucose concentration data substantiallywithout signal contribution due to non-glucose-related noise.

In an embodiment of the third aspect, the first working electrode andthe second working electrode are coaxial.

In an embodiment of the third aspect, at least one of the first workingelectrode and the second working electrode is twisted or helically woundto form at least a portion of the sensor.

In an embodiment of the third aspect, the first working electrode andthe second working electrode are twisted together to form an in vivoportion of the sensor.

In an embodiment of the third aspect, one of the first working electrodeand the second working electrode is deposited or plated over the otherof the first working electrode and the second working electrode.

In an embodiment of the third aspect, the first working electrode andthe second working electrode each comprise a first end and a second end,wherein the first ends are configured for insertion in the host, andwherein the second ends are configured for electrical connection tosensor electronics.

In an embodiment of the third aspect, the second ends are coaxial.

In an embodiment of the third aspect, the second ends are stepped.

In a fourth aspect, an analyte sensor configured for insertion into ahost for measuring an analyte in the host is provided, the sensorcomprising a first working electrode disposed beneath an activeenzymatic portion of a membrane; a second working electrode disposedbeneath an inactive-enzymatic or non-enzymatic portion of a membrane;and a non-conductive material located between the first workingelectrode and the second working electrode, wherein each of the firstworking electrode, the second working electrode, and the non-conductivematerial are configured provide at least two functions selected from thegroup consisting of electrical conductance, insulative property,structural support, and diffusion barrier.

In an embodiment of the fourth aspect, each of the first workingelectrode and the second working electrode are configured to provideelectrical conductance and structural support.

In an embodiment of the fourth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide electrical conductance and structural support.

In an embodiment of the fourth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide electrical conductance and a diffusion barrier.

In an embodiment of the fourth aspect, the non-conductive material isconfigured to provide an insulative property and structural support.

In an embodiment of the fourth aspect, the non-conductive material isconfigured to provide an insulative property and a diffusion barrier.

In an embodiment of the fourth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide a diffusion barrier and structural support

In an embodiment of the fourth aspect, the non-conductive material isconfigured to provide a diffusion barrier and structural support.

In an embodiment of the fourth aspect, the sensor further comprises atleast one of a reference electrode and a counter electrode.

In an embodiment of the fourth aspect, at least one of the referenceelectrode and the counter electrode, together with the first workingelectrode and the second working electrode, integrally form at least aportion of the sensor.

In an embodiment of the fourth aspect, at least one of the referenceelectrode and the counter electrode is located at a position remote fromthe first working electrode and the second working electrode.

In an embodiment of the fourth aspect, a surface area of at least one ofthe reference electrode and the counter electrode is at least six timesa surface area of at least one of the first working electrode and thesecond working electrode.

In an embodiment of the fourth aspect, the sensor is configured forimplantation into the host.

In an embodiment of the fourth aspect, the sensor is configured forsubcutaneous implantation in a tissue of the host.

In an embodiment of the fourth aspect, the sensor is configured forindwelling in a blood stream of the host.

In an embodiment of the fourth aspect, the sensor substantiallycontinuously measures an analyte concentration in the host.

In an embodiment of the fourth aspect, the sensor comprises a glucosesensor, and wherein the first working electrode is configured togenerate a first signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose related compoundshaving a first oxidation potential.

In an embodiment of the fourth aspect, the second working electrode isconfigured to generate a second signal associated with noise of theglucose sensor comprising signal contribution due to non-glucose relatedelectroactive compounds with an oxidation potential that substantiallyoverlaps with the first oxidation potential.

In an embodiment of the fourth aspect, the non-glucose relatedelectroactive species comprises at least one species selected from thegroup consisting of interfering species, non-reaction-related hydrogenperoxide, and other electroactive species.

In an embodiment of the fourth aspect, the sensor further compriseselectronics operably connected to the first working electrode and thesecond working electrode, and configured to provide the first signal andthe second signal to generate glucose concentration data substantiallywithout signal contribution due to non-glucose-related noise.

In an embodiment of the fourth aspect, the sensor further comprises anon-conductive material positioned between the first working electrodeand the second working electrode.

In an embodiment of the fourth aspect, the first working electrode, thesecond working electrode, and the non-conductive material integrallyform at least a portion of the sensor.

In an embodiment of the fourth aspect, the first working electrode andthe second working electrode each integrally form a substantial portionof the sensor configured for insertion in the host.

In an embodiment of the fourth aspect, the sensor further comprises areference electrode, wherein the first working electrode, the secondworking electrode, and the reference electrode each integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the fourth aspect, the sensor further comprises aninsulator, wherein the first working electrode, the second workingelectrode, and the insulator each integrally form a substantial portionof the sensor configured for insertion in the host.

In an embodiment of the fourth aspect, the sensor comprises a diffusionbarrier configured to substantially block diffusion of an analyte or aco-analyte between the first working electrode and the second workingelectrode.

In a fifth aspect, a glucose sensor configured for insertion into a hostfor measuring a glucose concentration in the host is provided, thesensor comprising a first working electrode configured to generate afirst signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential; a secondworking electrode configured to generate a second signal associated withnoise of the glucose sensor comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential; and anon-conductive material located between the first working electrode andthe second working electrode, wherein each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured provide at least two functions selected from the groupconsisting of electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In an embodiment of the fifth aspect, each of the first workingelectrode and the second working electrode are configured to provideelectrical conductance and structural support.

In an embodiment of the fifth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide electrical conductance and structural support.

In an embodiment of the fifth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide electrical conductance and a diffusion barrier.

In an embodiment of the fifth aspect, the sensor further comprises areference electrode, wherein the reference electrode is configured toprovide a diffusion barrier and structural support.

In an embodiment of the fifth aspect, the non-conductive material isconfigured to provide an insulative property and structural support.

In an embodiment of the fifth aspect, the non-conductive material isconfigured to provide an insulative property and a diffusion barrier.

In an embodiment of the fifth aspect, the non-conductive material isconfigured to provide a diffusion barrier and structural support.

In a sixth aspect, an analyte sensor configured for insertion into ahost for measuring an analyte in the host is provided, the sensorcomprising a first working electrode disposed beneath an activeenzymatic portion of a membrane; a second working electrode disposedbeneath an inactive-enzymatic or non-enzymatic portion of a membrane;and an insulator located between the first working electrode and thesecond working electrode, wherein the sensor comprises a diffusionbarrier configured to substantially block diffusion of at least one ofan analyte and a co-analyte between the first working electrode and thesecond working electrode.

In an embodiment of the sixth aspect, the diffusion barrier comprises aphysical diffusion barrier configured to physically block or spatiallyblock a substantial amount of diffusion of at least one of the analyteand the co-analyte between the first working electrode and the secondworking electrode.

In an embodiment of the sixth aspect, the physical diffusion barriercomprises the insulator.

In an embodiment of the sixth aspect, the physical diffusion barriercomprises the reference electrode.

In an embodiment of the sixth aspect, a dimension of the first workingelectrode and a dimension of the second working electrode relative to anin vivo portion of the sensor provide the physical diffusion barrier.

In an embodiment of the sixth aspect, the physical diffusion barriercomprises a membrane.

In an embodiment of the sixth aspect, the membrane is configured toblock diffusion of a substantial amount of at least one of the analyteand the co-analyte between the first working electrode and the secondworking electrode.

In an embodiment of the sixth aspect, the diffusion barrier comprises atemporal diffusion barrier configured to block or avoid a substantialamount of diffusion or reaction of at least one of the analyte and theco-analyte between the first and second working electrodes.

In an embodiment of the sixth aspect, the sensor further comprises apotentiostat configured to bias the first working electrode and thesecond working electrode at substantially overlapping oxidationpotentials, and wherein the temporal diffusion barrier comprises pulsedpotentials of the first working electrode and the second workingelectrode to block or avoid a substantial amount of diffusion orreaction of at least one of the analyte and the co-analyte between thefirst working electrode and the second working electrode.

In an embodiment of the sixth aspect, the sensor further comprises apotentiostat configured to bias the first working electrode and thesecond working electrode at substantially overlapping oxidationpotentials, and wherein the temporal diffusion barrier comprisesoscillating bias potentials of the first working electrode and thesecond working electrode to block or avoid a substantial amount ofdiffusion or reaction of at least one of the analyte and the co-analytebetween the first working electrode and the second working electrode.

In an embodiment of the sixth aspect, the analyte sensor is configuredto indwell in a blood stream of the host, and wherein the diffusionbarrier comprises a configuration of the first working electrode and thesecond working electrode that provides a flow path diffusion barrierconfigured to block or avoid a substantial amount of diffusion of atleast one of the analyte and the co-analyte between the first workingelectrode and the second working electrode.

In an embodiment of the sixth aspect, the flow path diffusion barriercomprises a location of the first working electrode configured to beupstream from the second working electrode when inserted into the bloodstream.

In an embodiment of the sixth aspect, the flow path diffusion barriercomprises a location of the first working electrode configured to bedownstream from the second working electrode when inserted into theblood stream.

In an embodiment of the sixth aspect, the flow path diffusion barriercomprises an offset of the first working electrode relative to thesecond working electrode when inserted into the blood stream.

In an embodiment of the sixth aspect, the flow path diffusion barrier isconfigured to utilize a shear of a blood flow of the host between thefirst working electrode and the second working electrode when insertedinto the blood stream.

In an embodiment of the sixth aspect, the sensor is a glucose sensor,and wherein the diffusion barrier is configured to substantially blockdiffusion of at least one of glucose and hydrogen peroxide between thefirst working electrode and the second working electrode.

In an embodiment of the sixth aspect, the sensor further comprises atleast one of a reference electrode and a counter electrode.

In an embodiment of the sixth aspect, the reference electrode or thecounter electrode, together with the first working electrode, the secondworking electrode and the insulator, integrally form at least a portionof the sensor.

In an embodiment of the sixth aspect, the reference electrode or thecounter electrode is located at a position remote from the first workingelectrode and the second working electrode.

In an embodiment of the sixth aspect, a surface area of at least one ofthe reference electrode and the counter electrode is at least six timesa surface area of at least one of the first working electrode and thesecond working electrode.

In an embodiment of the sixth aspect, the sensor is configured forimplantation into the host.

In an embodiment of the sixth aspect, the sensor is configured forsubcutaneous implantation in a tissue of the host.

In an embodiment of the sixth aspect, the sensor is configured forindwelling in a blood stream of the host.

In an embodiment of the sixth aspect, sensor substantially continuouslymeasures an analyte concentration in the host.

In an embodiment of the sixth aspect, the analyte sensor comprises aglucose sensor and wherein the first working electrode is configured togenerate a first signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential.

In an embodiment of the sixth aspect, the second working electrode isconfigured to generate a second signal associated with noise of theglucose sensor comprising signal contribution due to non-glucose relatedelectroactive compounds with an oxidation potential that substantiallyoverlaps with the first oxidation potential.

In an embodiment of the sixth aspect, the non-glucose relatedelectroactive species comprise at least one species selected from thegroup consisting of interfering species, non-reaction-related hydrogenperoxide, and other electroactive species.

In an embodiment of the sixth aspect, the sensor further compriseselectronics operably connected to the first working electrode and thesecond working electrode, and configured to provide the first signal andthe second signal to generate glucose concentration data substantiallywithout signal contribution due to non-glucose-related noise.

In an embodiment of the sixth aspect, the first working electrode, thesecond working electrode, and the insulator integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the sixth aspect, the sensor further comprises areference electrode, wherein the first working electrode, the secondworking electrode, and the reference electrode integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the sixth aspect, each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured provide at least two functions selected from the groupconsisting of electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In a seventh aspect, a glucose sensor configured for insertion into ahost for measuring a glucose concentration in the host is provided, thesensor comprising a first working electrode configured to generate afirst signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential; a secondworking electrode configured to generate a second signal associated withnoise of the glucose sensor comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential; and anon-conductive material located between the first working electrode andthe second working electrode, wherein the sensor comprises a diffusionbarrier configured to substantially block diffusion of at least one ofthe analyte and the co-analyte between the first working electrode andthe second working electrode.

In an embodiment of the seventh aspect, the diffusion barrier comprisesa physical diffusion barrier configured to physically or spatially blocka substantial amount of diffusion of at least one of the analyte and theco-analyte between the first working electrode and the second workingelectrode.

In an embodiment of the seventh aspect, the diffusion barrier comprisesa temporal diffusion barrier configured to block or avoid a substantialamount of diffusion or reaction of at least one of the analyte and theco-analyte between the first working electrode and the second workingelectrode.

In an embodiment of the seventh aspect, the analyte sensor is configuredto indwell in a blood stream of the host, and wherein the diffusionbarrier comprises a configuration of the first working electrode and thesecond working electrode that provides a flow path diffusion barrierconfigured to block or avoid a substantial amount of diffusion of atleast one of the analyte and the co-analyte between the first workingelectrode and the second working electrode.

In an embodiment of the seventh aspect, the sensor further comprises atleast one of a reference electrode and a counter electrode.

In an embodiment of the seventh aspect, the sensor is configured forimplantation into the host.

In an embodiment of the seventh aspect, the sensor substantiallycontinuously measures an analyte concentration in the host.

In an embodiment of the seventh aspect, the sensor further compriseselectronics operably connected to the first working electrode and thesecond working electrode, and configured to provide the first signal andthe second signal to generate glucose concentration data substantiallywithout signal contribution due to non-glucose-related noise.

In an embodiment of the seventh aspect, the first working electrode, thesecond working electrode, and the insulator integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the seventh aspect, each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured provide at least two functions selected from the groupconsisting of: electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In an eighth aspect, a glucose sensor system configured for insertioninto a host for measuring a glucose concentration in the host isprovided, the sensor comprising a first working electrode configured togenerate a first signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and non-glucose relatedelectroactive compounds having a first oxidation potential; a secondworking electrode configured to generate a second signal associated withnoise of the glucose sensor comprising signal contribution due tonon-glucose related electroactive compounds with an oxidation potentialthat substantially overlaps with the first oxidation potential; andelectronics operably connected to the first working electrode and thesecond working electrode and configured to process the first signal andthe second signal to generate a glucose concentration substantiallywithout signal contribution due to non-glucose related noise.

In an embodiment of the eighth aspect, the non-glucose related noise issubstantially non-constant.

In an embodiment of the eighth aspect, the electronics are configured tosubstantially remove noise caused by mechanical factors.

In an embodiment of the eighth aspect, the mechanical factors areselected from the group consisting of macro-motion of the sensor,micro-motion of the sensor, pressure on the sensor, and stress on thesensor.

In an embodiment of the eighth aspect, the first working electrode andthe second working electrode are configured to substantially equallymeasure noise due to mechanical factors, whereby noise caused bymechanical factors is substantially removed.

In an embodiment of the eighth aspect, the electronics are configured tosubstantially remove noise caused by at least one of biochemical factorsand chemical factors.

In an embodiment of the eighth aspect, the at least one of thebiochemical factors and the chemical factors are substantiallynon-constant and are selected from the group consisting of compoundswith electroactive acidic groups, compounds with electroactive aminegroups, compounds with electroactive sulfhydryl groups, urea, lacticacid, phosphates, citrates, peroxides, amino acids, amino acidprecursors, amino acid break-down products, nitric oxide, nitricoxide-donors, nitric oxide-precursors, electroactive species producedduring cell metabolism, electroactive species produced during woundhealing, and electroactive species that arise during body pH changes.

In an embodiment of the eighth aspect, the first working electrode andthe second working electrode are configured to substantially equallymeasure noise due to at least one of the biochemical factors and thechemical factors whereby noise caused by at least one of the biochemicalfactors and the chemical factors can be substantially removed.

In an embodiment of the eighth aspect, the electronics are configured tosubtract the second signal from the first signal, whereby a differentialsignal comprising at least one glucose sensor data point is determined.

In an embodiment of the eighth aspect, the electronics comprise adifferential amplifier configured to electronically subtract the secondsignal from the first signal.

In an embodiment of the eighth aspect, the electronics comprise at leastone of hardware and software configured to digitally subtract the secondsignal from the first signal.

In an embodiment of the eighth aspect, the first working electrode andthe second working electrode are configured to be impacted by mechanicalfactors and biochemical factors to substantially the same extent.

In an embodiment of the eighth aspect, the first working electrode andthe second working electrode have a configuration selected from thegroup consisting of coaxial, helically twisted, bundled, symmetrical,and combinations thereof.

In an embodiment of the eighth aspect, the sensor further comprises anon-conductive material positioned between the first working electrodeand the second working electrode.

In an embodiment of the eighth aspect, each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured provide at least two functions selected from the groupconsisting of electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In an embodiment of the eighth aspect, the sensor comprises a diffusionbarrier configured to substantially block diffusion of at least one ofthe analyte and the co-analyte between the first working electrode andthe second working electrode.

In an embodiment of the eighth aspect, the first working electrode, thesecond working electrode, and the insulator integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the eighth aspect, the sensor further comprises areference electrode, wherein the first working electrode, the secondworking electrode, and the reference electrode integrally form asubstantial portion of the sensor configured for insertion in the host.

In a ninth aspect, an analyte sensor configured for insertion into ahost for measuring an analyte in the host is provided, the sensorcomprising a first working electrode disposed beneath an activeenzymatic portion of a membrane; a second working electrode disposedbeneath an inactive-enzymatic or non-enzymatic portion of a membrane,wherein the first working electrode and the second working electrode areconfigured to substantially equally measure non-analyte related noise,whereby the noise is substantially removed; and electronics operablyconnected to the first working electrode and the second workingelectrode, and configured to process the first signal and the secondsignal to generate sensor analyte data substantially without signalcontribution due to non-analyte related noise.

In an embodiment of the ninth aspect, the non-glucose related noise issubstantially non-constant.

In an embodiment of the ninth aspect, the non-analyte related noise isdue to a factor selected from the group consisting of mechanicalfactors, biochemical factors, chemical factors, and combinationsthereof.

In an embodiment of the ninth aspect, the electronics are configured tosubstantially remove noise caused by mechanical factors.

In an embodiment of the ninth aspect, the mechanical factors areselected from the group consisting of macro-motion of the sensor,micro-motion of the sensor, pressure on the sensor, and stress on thesensor.

In an embodiment of the ninth aspect, the first working electrode andthe second working electrode are configured to substantially equallymeasure noise due to mechanical factors, whereby noise caused bymechanical factors can be substantially removed.

In an embodiment of the ninth aspect, the electronics are configured tosubstantially remove noise caused by at least one of biochemical factorsand chemical factors.

In an embodiment of the ninth aspect, at least one of the biochemicalfactors and the chemical factors are substantially non-constant and areselected from the group consisting of compounds with electroactiveacidic groups, compounds with electroactive amine groups, compounds withelectroactive sulfhydryl groups, urea, lactic acid, phosphates,citrates, peroxides, amino acids, amino acid precursors, amino acidbreak-down products, nitric oxide, nitric oxide-donors, nitricoxide-precursors, electroactive species produced during cell metabolism,electroactive species produced during wound healing, and electroactivespecies that arise during body pH changes.

In an embodiment of the ninth aspect, the first working electrode andthe second working electrode are configured to substantially equallymeasure noise due to at least one of biochemical factors and chemicalfactors, whereby noise caused by at least one of the biochemical factorsand the chemical factors is substantially removed.

In an embodiment of the ninth aspect, the sensor further comprises atleast one of a reference electrode and a counter electrode.

In an embodiment of the ninth aspect, at least one of the referenceelectrode and the counter electrode, together with the first workingelectrode and the second working electrode, integrally form at least aportion of the sensor.

In an embodiment of the ninth aspect, at least one of the referenceelectrode and the counter electrode is located at a position remote fromthe first working electrode and the second working electrode.

In an embodiment of the ninth aspect, a surface area of at least one ofthe reference electrode and the counter electrode is at least six timesa surface area of at least one of the first working electrode and thesecond working electrode.

In an embodiment of the ninth aspect, the sensor is configured forimplantation into the host.

In an embodiment of the ninth aspect, the sensor is configured forsubcutaneous implantation in a tissue of the host.

In an embodiment of the ninth aspect, the sensor is configured forindwelling in a blood stream of the host.

In an embodiment of the ninth aspect, the sensor substantiallycontinuously measures an analyte concentration of the host.

In an embodiment of the ninth aspect, the analyte sensor comprises aglucose sensor, and wherein the first working electrode is configured togenerate a first signal associated with glucose and non-glucose relatedelectroactive compounds, the glucose and the non-glucose relatedelectroactive compounds having a first oxidation potential.

In an embodiment of the ninth aspect, the second working electrode isconfigured to generate a second signal associated with noise of theglucose sensor comprising signal contribution due to non-glucose relatedelectroactive compounds with an oxidation potential that substantiallyoverlaps with the first oxidation potential.

In an embodiment of the ninth aspect, the non-glucose relatedelectroactive species comprises at least one species selected from thegroup consisting of interfering species, non-reaction-related hydrogenperoxide, and other electroactive species.

In an embodiment of the ninth aspect, the sensor further comprises anon-conductive material positioned between the first working electrodeand the second working electrode.

In an embodiment of the ninth aspect, each of the first workingelectrode, the second working electrode, and the non-conductive materialare configured provide at least two functions selected from the groupconsisting of: electrical conductance, insulative property, structuralsupport, and diffusion barrier.

In an embodiment of the ninth aspect, the sensor comprises a diffusionbarrier configured to substantially block diffusion of at least one ofan analyte and a co-analyte between the first working electrode and thesecond working electrode.

In an embodiment of the ninth aspect, the first working electrode, thesecond working electrode, and the insulator integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the ninth aspect, the sensor further comprises areference electrode, wherein the first working electrode, the secondworking electrode, and the reference electrode integrally form asubstantial portion of the sensor configured for insertion in the host.

In an embodiment of the ninth aspect, the first working electrode andthe second working electrode are configured to be impacted by mechanicalfactors and biochemical factors to substantially the same extent.

In an embodiment of the ninth aspect, the first working electrode andthe second working electrode have a configuration selected from thegroup consisting of coaxial, helically twisted, bundled, symmetrical,and combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of a continuous analyte sensor, includingan implantable body with a membrane system disposed thereon

FIG. 1B is an expanded view of an alternative embodiment of a continuousanalyte sensor, illustrating the in vivo portion of the sensor.

FIG. 2A is a schematic view of a membrane system in one embodiment,configured for deposition over the electroactive surfaces of the analytesensor of FIG. 1A.

FIG. 2B is a schematic view of a membrane system in an alternativeembodiment, configured for deposition over the electroactive surfaces ofthe analyte sensor of FIG. 1B.

FIG. 3A which is a cross-sectional exploded schematic view of a sensingregion of a continuous glucose sensor in one embodiment wherein anactive enzyme of an enzyme domain is positioned only over theglucose-measuring working electrode.

FIG. 3B is a cross-sectional exploded schematic view of a sensing regionof a continuous glucose sensor in another embodiment, wherein an activeportion of the enzyme within the enzyme domain positioned over theauxiliary working electrode has been deactivated.

FIG. 4 is a block diagram that illustrates continuous glucose sensorelectronics in one embodiment.

FIG. 5 is a drawing of a receiver for the continuous glucose sensor inone embodiment.

FIG. 6 is a block diagram of the receiver electronics in one embodiment.

FIG. 7A1 is a schematic of one embodiment of a coaxial sensor havingaxis A-A.

FIG. 7A2 is a cross-section of the sensor shown in FIG. 7A1.

FIG. 7B is a schematic of another embodiment of a coaxial sensor.

FIG. 7C is a schematic of one embodiment of a sensor having threeelectrodes.

FIG. 7D is a schematic of one embodiment of a sensor having sevenelectrodes.

FIG. 7E is a schematic of one embodiment of a sensor having two pairs ofelectrodes and insulating material.

FIG. 7F is a schematic of one embodiment of a sensor having twoelectrodes separated by a reference electrode or insulating material.

FIG. 7G is a schematic of another embodiment of a sensor having twoelectrodes separated by a reference electrode or insulating material.

FIG. 7H is a schematic of another embodiment of a sensor having twoelectrodes separated by a reference electrode or insulating material.

FIG. 7I is a schematic of another embodiment of a sensor having twoelectrodes separated by reference electrodes or insulating material.

FIG. 7J is a schematic of one embodiment of a sensor having twoelectrodes separated by a substantially X-shaped reference electrode orinsulating material.

FIG. 7K is a schematic of one embodiment of a sensor having twoelectrodes coated with insulating material, wherein one electrode has aspace for enzyme, the electrodes are separated by a distance D andcovered by a membrane system.

FIG. 7L is a schematic of one embodiment of a sensor having twoelectrodes embedded in an insulating material.

FIG. 7M is a schematic of one embodiment of a sensor having multipleworking electrodes and multiple reference electrodes.

FIG. 7N is a schematic of one step of the manufacture of one embodimentof a sensor having, embedded in insulating material, two workingelectrodes separated by a reference electrode, wherein the sensor istrimmed to a final size and/or shape.

FIG. 8A is a schematic on one embodiment of a sensor having two workingelectrodes coated with insulating material, and separated by a referenceelectrode.

FIG. 8B is a schematic of the second end (e.g., ex vivo terminus) of thesensor of FIG. 8A having a stepped connection to the sensor electronics.

FIG. 9A is a schematic of one embodiment of a sensor having two workingelectrodes and a substantially cylindrical reference electrode therearound, wherein the second end (the end connected to the sensorelectronics) of the sensor is stepped.

FIG. 9B is a schematic of one embodiment of a sensor having two workingelectrodes and an electrode coiled there around, wherein the second end(the end connected to the sensor electronics) of the sensor is stepped.

FIG. 10 is a schematic illustrating metabolism of glucose by GlucoseOxidase (GOx) and one embodiment of a diffusion barrier D thatsubstantially prevents the diffusion of H₂O₂ produced on a first side ofthe sensor (e.g., from a first electrode that has active GOx) to asecond side of the sensor (e.g., to the second electrode that lacksactive GOx).

FIG. 11 is a schematic illustrating one embodiment of a triple helicalcoaxial sensor having a stepped second terminus for engaging the sensorelectronics.

FIG. 12 is a graph that illustrates in vitro signal (raw counts)detected from a sensor having three bundled wire electrodes withstaggered working electrodes. Plus GOx (thick line)=the electrode withactive GOx. No GOx (thin line)=the electrode with inactive or no GOx.

FIG. 13 is a graph that illustrates in vitro signal (counts) detectedfrom a sensor having the configuration of the embodiment shown in FIG.7J (silver/silver chloride X-wire reference electrode separating twoplatinum wire working electrodes). Plus GOx (thick line)=the electrodewith active GOx. No GOx (thin line)=the electrode with inactive or noGOx.

FIG. 14 is a graph that illustrates an in vitro signal (counts) detectedfrom a dual-electrode sensor with a bundled configuration similar tothat shown in FIG. 7C (two platinum working electrodes and onesilver/silver chloride reference electrode, not twisted).

FIG. 15 is a graph that illustrates an in vivo signal (counts) detectedfrom a dual-electrode sensor with a bundled configuration similar tothat shown in FIG. 7C (two platinum working electrodes, not twisted, andone remotely disposed silver/silver chloride reference electrode).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the disclosed invention, anumber of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to a substance or chemical constituent ina biological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes mayinclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensor heads, devices, and methods disclosedherein is glucose. However, other analytes are contemplated as well,including but not limited to acarboxyprothrombin; acylcarnitine; adeninephosphoribosyl transferase; adenosine deaminase; albumin;alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-13hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, analyte-6-phosphate dehydrogenase,hemoglobinopathies, A,S,C,E, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free ß-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; analyte-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I; 17alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, ß);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids may also constitute analytes in certain embodiments. The analytemay be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte may be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body may also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and5-Hydroxyindoleacetic acid (FHIAA).

The term “continuous glucose sensor” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to a device thatcontinuously or continually measures glucose concentration, for example,at time intervals ranging from fractions of a second up to, for example,1, 2, or 5 minutes, or longer. It should be understood that continuousglucose sensors can continually measure glucose concentration withoutrequiring user initiation and/or interaction for each measurement, suchas described with reference to U.S. Pat. No. 6,001,067, for example.

The phrase “continuous glucose sensing” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to the period inwhich monitoring of plasma glucose concentration is continuously orcontinually performed, for example, at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes, or longer.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a sample of a host body, forexample, blood, interstitial fluid, spinal fluid, saliva, urine, tears,sweat, tissue, and the The term “host” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to plants or animals,for example humans.

The term “biointerface membrane” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can include one or more domains and is typicallyconstructed of materials of a few microns thickness or more, which canbe placed over the sensing region to keep host cells (for example,macrophages) from gaining proximity to, and thereby damaging themembrane system or forming a barrier cell layer and interfering with thetransport of glucose across the tissue-device interface.

The term “membrane system” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a permeable or semi-permeablemembrane that can be comprised of one or more domains and is typicallyconstructed of materials of a few microns thickness or more, which maybe permeable to oxygen and are optionally permeable to glucose. In oneexample, the membrane system comprises an immobilized glucose oxidaseenzyme, which enables an electrochemical reaction to occur to measure aconcentration of glucose.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to regions of a membrane that can be layers,uniform or non-uniform gradients (for example, anisotropic), functionalaspects of a material, or provided as portions of the membrane.

The term “copolymer” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to polymers having two or more differentrepeat units and includes copolymers, terpolymers, tetrapolymers, andthe like.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. In oneembodiment, the sensing region generally comprises a non-conductivebody, at least one electrode, a reference electrode and a optionally acounter electrode passing through and secured within the body forming anelectrochemically reactive surface at one location on the body and anelectronic connection at another location on the body, and a membranesystem affixed to the body and covering the electrochemically reactivesurface. In another embodiment, the sensing region generally comprises anon-conductive body, a working electrode (anode), a reference electrode(optionally can be remote from the sensing region), an insulatordisposed therebetween, and a multi-domain membrane affixed to the bodyand covering the electrochemically reactive surfaces of the working andoptionally reference electrodes.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and it is not to be limited to a specialor customized meaning), and refers without limitation to the surface ofan electrode where an electrochemical reaction takes place. In oneembodiment, a working electrode measures hydrogen peroxide creating ameasurable electronic current.

The term “electrochemical cell” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a device in which chemicalenergy is converted to electrical energy. Such a cell typically consistsof two or more electrodes held apart from each other and in contact withan electrolyte solution. Connection of the electrodes to a source ofdirect electric current renders one of them negatively charged and theother positively charged. Positive ions in the electrolyte migrate tothe negative electrode (cathode) and there combine with one or moreelectrons, losing part or all of their charge and becoming new ionshaving lower charge or neutral atoms or molecules; at the same time,negative ions migrate to the positive electrode (anode) and transfer oneor more electrons to it, also becoming new ions or neutral particles.The overall effect of the two processes is the transfer of electronsfrom the negative ions to the positive ions, a chemical reaction.

The term “electrode” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to a conductor through which electricityenters or leaves something such as a battery or a piece of electricalequipment. In one embodiment, the electrodes are the metallic portionsof a sensor (e.g., electrochemically reactive surfaces) that are exposedto the extracellular milieu, for detecting the analyte. In someembodiments, the term electrode includes the conductive wires or tracesthat electrically connect the electrochemically reactive surface toconnectors (for connecting the sensor to electronics) or to theelectronics.

The term “enzyme” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a protein or protein-based molecule thatspeeds up a chemical reaction occurring in a living thing. Enzymes mayact as catalysts for a single reaction, converting a reactant (alsocalled an analyte herein) into a specific product. In one exemplaryembodiment of a glucose oxidase-based glucose sensor, an enzyme, glucoseoxidase (GOX) is provided to react with glucose (the analyte) and oxygento form hydrogen peroxide.

The term “co-analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to a molecule required in an enzymaticreaction to react with the analyte and the enzyme to form the specificproduct being measured. In one exemplary embodiment of a glucose sensor,an enzyme, glucose oxidase (GOX) is provided to react with glucose andoxygen (the co-analyte) to form hydrogen peroxide.

The term “constant analyte” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to an analyte that remainsrelatively constant over a time period, for example over an hour to aday as compared to other variable analytes. For example, in a personwith diabetes, oxygen and urea may be relatively constant analytes inparticular tissue compartments relative to glucose, which is known tooscillate between about 40 and 400 mg/dL during a 24-hour cycle.Although analytes such as oxygen and urea are known to oscillate to alesser degree, for example due to physiological processes in a host,they are substantially constant, relative to glucose, and can bedigitally filtered, for example low pass filtered, to minimize oreliminate any relatively low amplitude oscillations. Constant analytesother than oxygen and urea are also contemplated.

The term “proximal” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to near to a point of reference such as anorigin or a point of attachment. For example, in some embodiments of amembrane system that covers an electrochemically reactive surface, theelectrolyte domain is located more proximal to the electrochemicallyreactive surface than the resistance domain.

The term “distal” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to spaced relatively far from a point ofreference, such as an origin or a point of attachment. For example, insome embodiments of a membrane system that covers an electrochemicallyreactive surface, a resistance domain is located more distal to theelectrochemically reactive surfaces than the electrolyte domain.

The term “substantially” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a sufficient amount thatprovides a desired function. For example, the interference domain of thepreferred embodiments is configured to resist a sufficient amount ofinterfering species such that tracking of glucose levels can beachieved, which may include an amount greater than 50 percent, an amountgreater than 60 percent, an amount greater than 70 percent, an amountgreater than 80 percent, or an amount greater than 90 percent ofinterfering species.

The term “computer” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to machine that can be programmed tomanipulate data.

The term “modem” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to an electronic device for converting betweenserial data from a computer and an audio signal suitable fortransmission over a telecommunications connection to another modem.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to acomputer system, state machine, processor, or the like designed toperform arithmetic and logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The term “ROM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to read-only memory, which is a type of datastorage device manufactured with fixed contents. ROM is broad enough toinclude EEPROM, for example, which is electrically erasable programmableread-only memory (ROM).

The term “RAM” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a data storage device for which the orderof access to different locations does not affect the speed of access.RAM is broad enough to include SRAM, for example, which is static randomaccess memory that retains data bits in its memory as long as power isbeing supplied.

The term “A/D Converter” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to hardware and/or software thatconverts analog electrical signals into corresponding digital signals.

The term “RF transceiver” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a radio frequency transmitterand/or receiver for transmitting and/or receiving signals.

The terms “raw data stream” and “data stream” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and they are not to be limited to aspecial or customized meaning), and refer without limitation to ananalog or digital signal directly related to the analyte concentrationmeasured by the analyte sensor. In one example, the raw data stream isdigital data in “counts” converted by an A/D converter from an analogsignal (for example, voltage or amps) representative of an analyteconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous analyte sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.In some embodiments, raw data includes one or more values (e.g., digitalvalue) representative of the current flow integrated over time (e.g.,integrated value), for example, using a charge counting device, or thelike.

The term “counts” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.In one example, a raw data stream measured in counts is directly relatedto a voltage (for example, converted by an A/D converter), which isdirectly related to current from a working electrode.

The term “electronic circuitry” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the components (for example,hardware and/or software) of a device configured to process data. In thecase of an analyte sensor, the data includes biological informationobtained by a sensor regarding the concentration of the analyte in abiological fluid. U.S. Pat. Nos. 4,757,022, 5,497,772 and 4,787,398,which are hereby incorporated by reference in their entirety, describesuitable electronic circuits that can be utilized with devices ofcertain embodiments.

The term “potentiostat” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to an electrical system thatapplies a potential between the working and reference electrodes of atwo- or three-electrode cell at a preset value and measures the currentflow through the working electrode. Typically, the potentiostat forceswhatever current is necessary to flow between the working and referenceor counter electrodes to keep the desired potential, as long as theneeded cell voltage and current do not exceed the compliance limits ofthe potentiostat.

The terms “operably connected” and “operably linked” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to one ormore components being linked to another component(s) in a manner thatallows transmission of signals between the components. For example, oneor more electrodes can be used to detect the amount of glucose in asample and convert that information into a signal; the signal can thenbe transmitted to an electronic circuit. In this case, the electrode is“operably linked” to the electronic circuit. These terms are broadenough to include wired and wireless connectivity.

The term “smoothing” and “filtering” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and they are not to be limited to a specialor customized meaning), and refer without limitation to modification ofa set of data to make it smoother and more continuous and remove ordiminish outlying points, for example, by performing a moving average ofthe raw data stream.

The term “algorithm” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to the computational processes (forexample, programs) involved in transforming information from one stateto another, for example using computer processing.

The term “regression” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to finding a line in which a set of datahas a minimal measurement (for example, deviation) from that line.Regression can be linear, non-linear, first order, second order, and soforth. One example of regression is least squares regression.

The term “pulsed amperometric detection” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and it is not to be limited to a special orcustomized meaning), and refers without limitation to an electrochemicalflow cell and a controller, which applies the potentials and monitorscurrent generated by the electrochemical reactions. The cell can includeone or multiple working electrodes at different applied potentials.Multiple electrodes can be arranged so that they face thechromatographic flow independently (parallel configuration), orsequentially (series configuration).

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to the relationship and/or theprocess of determining the relationship between the sensor data andcorresponding reference data, which may be used to convert sensor datainto meaningful values substantially equivalent to the reference. Insome embodiments, namely in continuous analyte sensors, calibration maybe updated or recalibrated over time if changes in the relationshipbetween the sensor and reference data occur, for example due to changesin sensitivity, baseline, transport, metabolism, or the like.

The term “sensor analyte values” and “sensor data” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation to datareceived from a continuous analyte sensor, including one or moretime-spaced sensor data points.

The term “reference analyte values” and “reference data” as used hereinare broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and they are not to belimited to a special or customized meaning), and refer withoutlimitation to data from a reference analyte monitor, such as a bloodglucose meter, or the like, including one or more reference data points.In some embodiments, the reference glucose values are obtained from aself-monitored blood glucose (SMBG) test (for example, from a finger orforearm blood test) or an YSI (Yellow Springs Instruments) test, forexample.

The term “matched data pairs” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to reference data (for example,one or more reference analyte data points) matched with substantiallytime corresponding sensor data (for example, one or more sensor datapoints).

The terms “interferants” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and they are not to be limited toa special or customized meaning), and refer without limitation toeffects and/or species that interfere with the measurement of an analyteof interest in a sensor to produce a signal that does not accuratelyrepresent the analyte measurement. In one example of an electrochemicalsensor, interfering species are compounds with an oxidation potentialthat overlaps with the analyte to be measured, producing a falsepositive signal. In another example of an electrochemical sensor,interfering species are substantially non-constant compounds (e.g., theconcentration of an interfering species fluctuates over time).Interfering species include but are not limited to compounds withelectroactive acidic, amine or sulfhydryl groups, urea, lactic acid,phosphates, citrates, peroxides, amino acids, amino acid precursors orbreak-down products, nitric oxide (NO), NO-donors, NO-precursors,acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acidelectroactive species produced during cell metabolism and/or woundhealing, electroactive species that arise during body pH changes and thelike.

The term “bifunctional” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to having or serving twofunctions. For example, in a needle-type analyte sensor, a metal wire isbifunctional because it provides structural support and acts as anelectrical conductor.

The term “function” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to an action or use for which something issuited or designed.

The term “electrical conductor” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to materials that contain movablecharges of electricity. When an electric potential difference isimpressed across separate points on a conductor, the mobile chargeswithin the conductor are forced to move, and an electric current betweenthose points appears in accordance with Ohm's law.

Accordingly, the term “electrical conductance” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning) and refers without limitation to the propensity of amaterial to behave as an electrical conductor. In some embodiments, theterm refers to a sufficient amount of electrical conductance (e.g.,material property) to provide a necessary function (electricalconduction).

The terms “insulative properties,” “electrical insulator” and“insulator” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning) and referswithout limitation to the tendency of materials that lack mobile chargesto prevent movement of electrical charges between two points. In oneexemplary embodiment, an electrically insulative material may be placedbetween two electrically conductive materials, to prevent movement ofelectricity between the two electrically conductive materials. In someembodiments, the terms refer to a sufficient amount of insulativeproperty (e.g., of a material) to provide a necessary function(electrical insulation). The terms “insulator” and “non-conductivematerial” can be used interchangeably herein.

The term “structural support” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to the tendency of a material tokeep the sensor's structure stable or in place. For example, structuralsupport can include “weight bearing” as well as the tendency to hold theparts or components of a whole structure together. A variety ofmaterials can provide “structural support” to the sensor.

The term “diffusion barrier” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning) and refers without limitation to something that obstructs therandom movement of compounds, species, atoms, molecules, or ions fromone site in a medium to another. In some embodiments, a diffusionbarrier is structural, such as a wall that separates two workingelectrodes and substantially prevents diffusion of a species from oneelectrode to the other. In some embodiments, a diffusion barrier isspatial, such as separating working electrodes by a distancesufficiently large enough to substantially prevent a species at a firstelectrode from affecting a second electrode. In other embodiments, adiffusion barrier can be temporal, such as by turning the first andsecond working electrodes on and off, such that a reaction at a firstelectrode will not substantially affect the function of the secondelectrode.

The terms “integral,” “integrally,” “integrally formed,” integrallyincorporated,” “unitary” and “composite” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and they are not to be limited to a specialor customized meaning), and refer without limitation to the condition ofbeing composed of essential parts or elements that together make awhole. The parts are essential for completeness of the whole. In oneexemplary embodiment, at least a portion (e.g., the in vivo portion) ofthe sensor is formed from at least one platinum wire at least partiallycovered with an insulative coating, which is at least partiallyhelically wound with at least one additional wire, the exposedelectroactive portions of which are covered by a membrane system (seedescription of FIG. 1B or 9B); in this exemplary embodiment, eachelement of the sensor is formed as an integral part of the sensor (e.g.,both functionally and structurally).

The term “coaxial” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to having a common axis, having coincidentaxes or mounted on concentric shafts.

The term “twisted” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and it is not to be limited to a special or customized meaning),and refers without limitation to united by having one part or end turnedin the opposite direction to the other, such as, but not limited to thetwisted strands of fiber in a string, yarn, or cable.

The term “helix” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to a spiral or coil, or something in the formof a spiral or coil (e.g. a corkscrew or a coiled spring). In oneexample, a helix is a mathematical curve that lies on a cylinder or coneand makes a constant angle with the straight lines lying in the cylinderor cone. A “double helix” is a pair of parallel helices intertwinedabout a common axis, such as but not limited to that in the structure ofDNA.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device that isto be implanted or inserted into the host. In one exemplary embodiment,an in vivo portion of a transcutaneous sensor is a portion of the sensorthat is inserted through the host's skin and resides within the host.

The terms “background,” “baseline,” and “noise” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refer without limitation to acomponent of an analyte sensor signal that is not related to the analyteconcentration. In one example of a glucose sensor, the background iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation potentialthat overlaps with hydrogen peroxide). In some embodiments wherein acalibration is defined by solving for the equation y=mx+b, the value ofb represents the background of the signal. In general, the background(noise) comprises components related to constant and non-constantfactors.

The term “constant noise” and “constant background” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to thecomponent of the background signal that remains relatively constant overtime. For example, certain electroactive compounds found in the humanbody are relatively constant factors (e.g., baseline of the host'sphysiology) and do not significantly adversely affect accuracy of thecalibration of the glucose concentration (e.g., they can be relativelyconstantly eliminated using the equation y=mx+b). In some circumstances,constant background noise can slowly drift over time (e.g., increases ordecreases), however this drift need not adversely affect the accuracy ofa sensor, for example, because a sensor can be calibrated andre-calibrated and/or the drift measured and compensated for.

The term “non-constant noise” or non-constant background” as used hereinare broad terms, and are to be given their ordinary and customarymeaning to a person of ordinary skill in the art (and it is not to belimited to a special or customized meaning), and refer withoutlimitation to a component of the background signal that is relativelynon-constant, for example, transient and/or intermittent. For example,certain electroactive compounds, are relatively non-constant (e.g.,intermittent interferents due to the host's ingestion, metabolism, woundhealing, and other mechanical, chemical and/or biochemical factors),which create intermittent (e.g., non-constant) “noise” on the sensorsignal that can be difficult to “calibrate out” using a standardcalibration equations (e.g., because the background of the signal doesnot remain constant).

The terms “inactive enzyme” or “inactivated enzyme” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and it is not to be limited to aspecial or customized meaning), and refer without limitation to anenzyme (e.g., glucose oxidase, GOx) that has been rendered inactive(e.g., “killed” or “dead”) and has no enzymatic activity. Enzymes can beinactivated using a variety of techniques known in the art, such as butnot limited to heating, freeze-thaw, denaturing in organic solvent,acids or bases, cross-linking, genetically changing enzymaticallycritical amino acids, and the like. In some embodiments, a solutioncontaining active enzyme can be applied to the sensor, and the appliedenzyme subsequently inactivated by heating or treatment with aninactivating solvent.

The term “non-enzymatic” as used herein is a broad term, and is to begiven their ordinary and customary meaning to a person of ordinary skillin the art (and it is not to be limited to a special or customizedmeaning), and refers without limitation to a lack of enzyme activity. Insome embodiments, a “non-enzymatic” membrane portion contains no enzyme;while in other embodiments, the “non-enzymatic” membrane portioncontains inactive enzyme. In some embodiments, an enzyme solutioncontaining inactive enzyme or no enzyme is applied.

The term “GOx” as used herein is a broad term, and is to be given theirordinary and customary meaning to a person of ordinary skill in the art(and it is not to be limited to a special or customized meaning), andrefers without limitation to the enzyme Glucose Oxidase (e.g., GOx is anabbreviation).

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that can varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Overview

The preferred embodiments provide a continuous analyte sensor thatmeasures a concentration of the analyte of interest or a substanceindicative of the concentration or presence of the analyte. In someembodiments, the analyte sensor is an invasive, minimally invasive, ornon-invasive device, for example a subcutaneous, transdermal, orintravascular device. In some embodiments, the analyte sensor mayanalyze a plurality of intermittent biological samples. The analytesensor may use any method of analyte-measurement, including enzymatic,chemical, physical, electrochemical, spectrophotometric, polarimetric,calorimetric, radiometric, or the like.

In general, analyte sensors provide at least one working electrode andat least one reference electrode, which are configured to measure asignal associated with a concentration of the analyte in the host, suchas described in more detail below, and as appreciated by one skilled inthe art. The output signal is typically a raw data stream that is usedto provide a useful value of the measured analyte concentration in ahost to the patient or doctor, for example. However, the analyte sensorsof the preferred embodiments may further measure at least one additionalsignal. For example, in some embodiments, the additional signal isassociated with the baseline and/or sensitivity of the analyte sensor,thereby enabling monitoring of baseline and/or sensitivity changes thatmay occur in a continuous analyte sensor over time.

In general, continuous analyte sensors define a relationship betweensensor-generated measurements (for example, current in nA or digitalcounts after A/D conversion) and a reference measurement (for example,mg/dL or mmol/L) that are meaningful to a user (for example, patient ordoctor). In the case of an implantable enzyme-based electrochemicalglucose sensor, the sensing mechanism generally depends on phenomenathat are linear with glucose concentration, for example: (1) diffusionof glucose through a membrane system (for example, biointerface membraneand membrane system) situated between implantation site and theelectrode surface, (2) an enzymatic reaction within the membrane system(for example, membrane system), and (3) diffusion of the H₂O₂ to thesensor. Because of this linearity, calibration of the sensor can beunderstood by solving an equation:

y=mx+b

where y represents the sensor signal (counts), x represents theestimated glucose concentration (mg/dL), m represents the sensorsensitivity to glucose (counts/mg/dL), and b represents the baselinesignal (counts). Because both sensitivity m and baseline (background) bchange over time in vivo, calibration has conventionally required atleast two independent, matched data pairs (x₁, y₁; X₂, y₂) to solve form and b and thus allow glucose estimation when only the sensor signal, yis available. Matched data pairs can be created by matching referencedata (for example, one or more reference glucose data points from ablood glucose meter, or the like) with substantially time correspondingsensor data (for example, one or more glucose sensor data points) toprovide one or more matched data pairs, such as described in co-pendingU.S. Publication No. US-2005-0027463-A1.

Accordingly, in some embodiments, the sensing region is configured tomeasure changes in sensitivity of the analyte sensor over time, whichcan be used to trigger calibration, update calibration, avoid inaccuratecalibration (for example, calibration during unstable periods), and/ortrigger filtering of the sensor data. Namely, the analyte sensor isconfigured to measure a signal associated with a non-analyte constant inthe host. Preferably, the non-analyte constant signal is measuredbeneath the membrane system on the sensor. In one example of a glucosesensor, a non-glucose constant that can be measured is oxygen, wherein ameasured change in oxygen transport is indicative of a change in thesensitivity of the glucose signal, which can be measured by switchingthe bias potential of the working electrode, an auxiliaryoxygen-measuring electrode, an oxygen sensor, or the like, as describedin more detail elsewhere herein.

Alternatively or additionally, in some embodiments, the sensing regionis configured to measure changes in the amount of background noise(e.g., baseline) in the signal, which can be used to triggercalibration, update calibration, avoid inaccurate calibration (forexample, calibration during unstable periods), and/or trigger filteringof the sensor data. In one example of a glucose sensor, the baseline iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation potentialthat overlaps with hydrogen peroxide). Namely, the glucose sensor isconfigured to measure a signal associated with the baseline (allnon-glucose related current generated) measured by sensor in the host.In some embodiments, an auxiliary electrode located beneath anon-enzymatic portion of the membrane system is used to measure thebaseline signal. In some embodiments, the baseline signal is subtractedfrom the glucose signal (which includes the baseline) to obtain thesignal contribution substantially only due to glucose. Subtraction maybe accomplished electronically in the sensor using a differentialamplifier, digitally in the receiver, and/or otherwise in the hardwareor software of the sensor or receiver as is appreciated by one skilledin the art, and as described in more detail elsewhere herein.

One skilled in the art appreciates that the above-described sensitivityand baseline signal measurements can be combined to benefit from bothmeasurements in a single analyte sensor.

Preferred Sensor Components

In general, sensors of the preferred embodiments describe a variety ofsensor configurations, wherein each sensor generally comprises two ormore working electrodes, a reference and/or counter electrode, aninsulator, and a membrane system. In general, the sensors can beconfigured to continuously measure an analyte in a biological sample,for example, in subcutaneous tissue, in a host's blood flow, and thelike. Although a variety of exemplary embodiments are shown, one skilledin the art appreciates that the concepts and examples here can becombined, reduced, substituted, or otherwise modified in accordance withthe teachings of the preferred embodiments and/or the knowledge of oneskilled in the art.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A through9B, and 11) includes a first working electrode, wherein the workingelectrode is formed from known materials. In some embodiments, eachelectrode is formed from a fine wire with a diameter of from about 0.001or less to about 0.010 inches or more, for example, and is formed from,e.g., a plated insulator, a plated wire, or bulk electrically conductivematerial. In preferred embodiments, the working electrode comprises awire formed from a conductive material, such as platinum,platinum-iridium, palladium, graphite, gold, carbon, conductive polymer,alloys, or the like. Although the electrodes can by formed by a varietyof manufacturing techniques (bulk metal processing, deposition of metalonto a substrate, and the like), it can be advantageous to form theelectrodes from plated wire (e.g., platinum on steel wire) or bulk metal(e.g., platinum wire). It is believed that electrodes formed from bulkmetal wire provide superior performance (e.g., in contrast to depositedelectrodes), including increased stability of assay, simplifiedmanufacturability, resistance to contamination (e.g., which can beintroduced in deposition processes), and improved surface reaction(e.g., due to purity of material) without peeling or delamination.

Preferably, the working electrode is configured to measure theconcentration of an analyte. In an enzymatic electrochemical sensor fordetecting glucose, for example, the working electrode measures thehydrogen peroxide produced by an enzyme catalyzed reaction of theanalyte being detected and creates a measurable electronic current. Forexample, in the detection of glucose wherein glucose oxidase produceshydrogen peroxide as a byproduct, hydrogen peroxide (H₂O₂) reacts withthe surface of the working electrode producing two protons (2H⁺), twoelectrons (2e⁻) and one molecule of oxygen (O₂), which produces theelectronic current being detected.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A through9B, and 11) includes at least one additional working electrodeconfigured to measure a baseline (e.g., background noise) signal, tomeasure another analyte (e.g., oxygen), to generate oxygen, and/or as atransport-measuring electrode, all of which are described in more detailelsewhere herein. In general, the additional working electrode(s) can beformed as described with reference to the first working electrode. Inone embodiment, the auxiliary (additional) working electrode isconfigured to measure a background signal, including constant andnon-constant analyte signal components.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, and 7Athrough 9B) includes a reference and/or counter electrode. In general,the reference electrode has a configuration similar to that describedelsewhere herein with reference to the first working electrode, howevermay be formed from materials, such as silver, silver/silver chloride,calomel, and the like. In some embodiments, the reference electrode isintegrally formed with the one or more working electrodes, however otherconfigurations are also possible (e.g., remotely located on the host'sskin, or otherwise in bodily fluid contact). In some exemplaryembodiments (e.g., FIGS. 1B and 9B, the reference electrode is helicallywound around other component(s) of the sensor system. In somealternative embodiments, the reference electrode is disposed remotelyfrom the sensor, such as but not limited to on the host's skin, asdescribed herein.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A through9B, and 11) includes an insulator (e.g., non-conductive material) orsimilarly functional component. In some embodiments, one or moreelectrodes are covered with an insulating material, for example, anon-conductive polymer. Dip-coating, spray-coating, vapor-deposition, orother coating or deposition techniques can be used to deposit theinsulating material on the electrode(s). In some embodiments, theinsulator is a separate component of the system (e.g., see FIG. 7E) andcan be formed as is appreciated by one skilled in the art. In oneembodiment, the insulating material comprises parylene, which can be anadvantageous polymer coating for its strength, lubricity, and electricalinsulation properties. Generally, parylene is produced by vapordeposition and polymerization of para-xylylene (or its substitutedderivatives). In alternative embodiments, any suitable insulatingmaterial can be used, for example, fluorinated polymers,polyethyleneterephthalate, polyurethane, polyimide, other nonconductingpolymers, or the like. Glass or ceramic materials can also be employed.Other materials suitable for use include surface energy modified coatingsystems such as are marketed under the trade names AMC18, AMC148,AMC141, and AMC321 by Advanced Materials Components Express ofBellafonte, PA.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A through9B, and 11) includes exposed electroactive area(s). In embodimentswherein an insulator is disposed over one or more electrodes, a portionof the coated electrode(s) can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit),and the like, to expose the electroactive surfaces. Alternatively, aportion of the electrode can be masked prior to depositing the insulatorin order to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, a coating (e.g., parylene) without damaging, anunderlying conductor (e.g., platinum). One additional advantage ofsodium bicarbonate blasting includes its polishing action on the metalas it strips the polymer layer, thereby eliminating a cleaning step thatmight otherwise be necessary. In some embodiments, the tip (e.g., end)of the sensor is cut to expose electroactive surface areas, without aneed for removing insulator material from sides of insulated electrodes.In general, a variety of surfaces and surface areas can be exposed.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A through9B, and 11) includes a membrane system. Preferably, a membrane system isdeposited over at least a portion of the electroactive surfaces of thesensor (working electrode(s) and optionally reference electrode) andprovides protection of the exposed electrode surface from the biologicalenvironment, diffusion resistance (limitation) of the analyte if needed,a catalyst for enabling an enzymatic reaction, limitation or blocking ofinterferents, and/or hydrophilicity at the electrochemically reactivesurfaces of the sensor interface. Some examples of suitable membranesystems are described in U.S. Publication No. US-2005-0245799-A1.

In general, the membrane system includes a plurality of domains, forexample, one or more of an electrode domain 24, an optional interferencedomain 26, an enzyme domain 28 (for example, including glucose oxidase),and a resistance domain 30, as shown in FIGS. 2A and 2B, and can includea high oxygen solubility domain, and/or a bioprotective domain (notshown), such as is described in more detail in U.S. Publication No.US-2005-0245799-A1, and such as is described in more detail below. Themembrane system can be deposited on the exposed electroactive surfacesusing known thin film techniques (for example, vapor deposition,spraying, electro-depositing, dipping, or the like). In alternativeembodiments, however, other vapor deposition processes (e.g., physicaland/or chemical vapor deposition processes) can be useful for providingone or more of the insulating and/or membrane layers, includingultrasonic vapor deposition, electrostatic deposition, evaporativedeposition, deposition by sputtering, pulsed laser deposition, highvelocity oxygen fuel deposition, thermal evaporator deposition, electronbeam evaporator deposition, deposition by reactive sputtering molecularbeam epitaxy, atmospheric pressure chemical vapor deposition (CVD),atomic layer CVD, hot wire CVD, low-pressure CVD, microwaveplasma-assisted CVD, plasma-enhanced CVD, rapid thermal CVD, remoteplasma-enhanced CVD, and ultra-high vacuum CVD, for example. However,the membrane system can be disposed over (or deposited on) theelectroactive surfaces using any known method, as will be appreciated byone skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain 24 (FIGS. 2A-2B). The electrode domain is provided to ensure thatan electrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode, which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dryfilm” thickness refers to the thickness of a cured film cast from acoating formulation by standard coating techniques.

In certain embodiments, the electrode domain is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain is formed from ahydrophilic polymer such as polyvinylpyrrolidone (PVP). An electrodedomain formed from PVP has been shown to reduce break-in time of analytesensors; for example, a glucose sensor utilizing a cellulosic-basedinterference domain such as described in more detail below.

Preferably, the electrode domain is deposited by vapor deposition, spraycoating, dip coating, or other thin film techniques on the electroactivesurfaces of the sensor. In one preferred embodiment, the electrodedomain is formed by dip-coating the electroactive surfaces in anelectrode layer solution and curing the domain for a time of from about15 minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode layer solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode layersolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode layer solution provide a functionalcoating. However, values outside of those set forth above can beacceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes.

Although an independent electrode domain is described herein, in someembodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal. In preferred embodiments, an optional interferencedomain 26 is provided that substantially restricts, resists, or blocksthe flow of one or more interfering species (FIGS. 2A-2B). Some knowninterfering species for a glucose sensor, as described in more detailabove, include acetaminophen, ascorbic acid, bilirubin, cholesterol,creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa,salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, anduric acid. In general, the interference domain of the preferredembodiments is less permeable to one or more of the interfering speciesthan to the analyte, e.g., glucose.

In one embodiment, the interference domain is formed from one or morecellulosic derivatives. In general, cellulosic derivatives includepolymers such as cellulose acetate, cellulose acetate butyrate,2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate trimellitate, and the like.

In one preferred embodiment, the interference domain is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of about 10,000 daltons to about 75,000 daltons, preferably fromabout 15,000, 20,000, or 25,000 daltons to about 55,000, 60,000, 65,000,or 70,000 daltons, and more preferably about 20,000 daltons is employed.In certain embodiments, however, higher or lower molecular weights canbe preferred. Additionally, a casting solution or dispersion ofcellulose acetate butyrate at a weight percent of about 15% to about25%, preferably from about 15%, 16%, 17%, 18%, 19% to about 20%, 21%,22%, 23%, 24% or 25%, and more preferably about 18% is preferred.Preferably, the casting solution includes a solvent or solvent system,for example an acetone:ethanol solvent system. Higher or lowerconcentrations can be preferred in certain embodiments. A plurality oflayers of cellulose acetate butyrate can be advantageously combined toform the interference domain in some embodiments, for example, threelayers can be employed. It can be desirable to employ a mixture ofcellulose acetate butyrate components with different molecular weightsin a single solution, or to deposit multiple layers of cellulose acetatebutyrate from different solutions comprising cellulose acetate butyrateof different molecular weights, different concentrations, and/ordifferent chemistries (e.g., functional groups). It can also bedesirable to include additional substances in the casting solutions ordispersions, e.g., functionalizing agents, crosslinking agents, otherpolymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain is formed fromcellulose acetate. Cellulose acetate with a molecular weight of about30,000 daltons or less to about 100,000 daltons or more, preferably fromabout 35,000, 40,000, or 45,000 daltons to about 60,000, 65,000, 70,000,75,000, 80,000, 85,000, 90,000, or 95,000 daltons, and more preferablyabout 50,000 daltons is preferred. Additionally, a casting solution ordispersion of cellulose acetate at a weight percent of about 3% to about10%, preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5%to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about 8%is preferred. In certain embodiments, however, higher or lower molecularweights and/or cellulose acetate weight percentages can be preferred. Itcan be desirable to employ a mixture of cellulose acetates withmolecular weights in a single solution, or to deposit multiple layers ofcellulose acetate from different solutions comprising cellulose acetatesof different molecular weights, different concentrations, or differentchemistries (e.g., functional groups). It can also be desirable toinclude additional substances in the casting solutions or dispersionssuch as described in more detail above.

Layer(s) prepared from combinations of cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate can also be employed to form theinterference domain.

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain. As oneexample, a 5 wt % Nafion® casting solution or dispersion can be used incombination with a 8 wt % cellulose acetate casting solution ordispersion, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain of the preferred embodiments. Ingeneral, the formation of the interference domain on a surface utilizesa solvent or solvent system in order to solvate the cellulosicderivative (or other polymer) prior to film formation thereon. Inpreferred embodiments, acetone and ethanol are used as solvents forcellulose acetate; however one skilled in the art appreciates thenumerous solvents that are suitable for use with cellulosic derivatives(and other polymers). Additionally, one skilled in the art appreciatesthat the preferred relative amounts of solvent can be dependent upon thecellulosic derivative (or other polymer) used, its molecular weight, itsmethod of deposition, its desired thickness, and the like. However, apercent solute of from about 1% to about 25% is preferably used to formthe interference domain solution so as to yield an interference domainhaving the desired properties. The cellulosic derivative (or otherpolymer) used, its molecular weight, method of deposition, and desiredthickness can be adjusted, depending upon one or more other of theparameters, and can be varied accordingly as is appreciated by oneskilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of low molecular weight species.The interference domain is permeable to relatively low molecular weightsubstances, such as hydrogen peroxide, but restricts the passage ofhigher molecular weight substances, including glucose and ascorbic acid.Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Publication No. US-2005-0115832-A1,U.S. Publication No. US-2005-0176136-A1, U.S. Publication No.US-2005-0161346-A1, and U.S. Publication No. US-2005-0143635-A1. In somealternative embodiments, a distinct interference domain is not included.

In preferred embodiments, the interference domain is deposited directlyonto the electroactive surfaces of the sensor for a domain thickness offrom about 0.05 micron or less to about 20 microns or more, morepreferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.5,1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 1, 1.5 or 2 microns to about 2.5 or 3 microns. Thickermembranes can also be desirable in certain embodiments, but thinnermembranes are generally preferred because they have a lower impact onthe rate of diffusion of hydrogen peroxide from the enzyme membrane tothe electrodes.

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain is deposited by vapor deposition, spray coating, ordip coating. In one exemplary embodiment of a needle-type(transcutaneous) sensor such as described herein, the interferencedomain is formed by dip coating the sensor into an interference domainsolution using an insertion rate of from about 20 inches/min to about 60inches/min, preferably 40 inches/min, a dwell time of from about 0minute to about 5 seconds, preferably 0 seconds, and a withdrawal rateof from about 20 inches/minute to about 60 inches/minute, preferablyabout 40 inches/minute, and curing (drying) the domain from about 1minute to about 30 minutes, preferably from about 3 minutes to about 15minutes (and can be accomplished at room temperature or under vacuum(e.g., 20 to 30 mmHg)). In one exemplary embodiment including celluloseacetate butyrate interference domain, a 3-minute cure (i.e., dry) timeis preferred between each layer applied. In another exemplary embodimentemploying a cellulose acetate interference domain, a 15 minute cure(i.e., dry) time is preferred between each layer applied.

The dip process can be repeated at least one time and up to 10 times ormore. The preferred number of repeated dip processes depends upon thecellulosic derivative(s) used, their concentration, conditions duringdeposition (e.g., dipping) and the desired thickness (e.g., sufficientthickness to provide functional blocking of (or resistance to) certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In another exemplary embodiment, aninterference domain is formed of one relatively thicker layer ofcellulose acetate butyrate. In yet another exemplary embodiment, aninterference domain is formed of four relatively thinner layers ofcellulose acetate butyrate. In alternative embodiments, the interferencedomain can be formed using any known method and combination of celluloseacetate and cellulose acetate butyrate, as will be appreciated by oneskilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain. In some embodiments, theinterference domain of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 28 disposed more distally from the electroactive surfaces thanthe interference domain; however other configurations can be desirable(FIGS. 2A-2B). In the preferred embodiments, the enzyme domain providesan enzyme to catalyze the reaction of the analyte and its co-reactant,as described in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase(GOx), are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating isused to deposit the enzyme domain at room temperature, a preferredinsertion rate of from about 0.25 inch per minute to about 3 inches perminute, with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at under vacuum for 20 minutes. However, in some embodiments, theenzyme domain can be formed by dip coating and/or spray coating one ormore layers at a predetermined concentration of the coating solution,insertion rate, dwell time, withdrawal rate, and/or desired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain disposed more distal from the electroactive surfaces than theenzyme domain (FIGS. 2A-2B). Although the following description isdirected to a resistance domain for a glucose sensor, the resistancedomain can be modified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21(1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Publication No.US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In some embodiments, the resistance domain is formed from a siliconepolymer modified to allow analyte (e.g., glucose) transport.

In some embodiments, the resistance domain is formed from a siliconepolymer/hydrophobic-hydrophilic polymer blend. In one embodiment, Thehydrophobic-hydrophilic polymer for use in the blend may be any suitablehydrophobic-hydrophilic polymer, including but not limited to componentssuch as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers such as polyethyleneglycol or polypropylene oxide, and copolymers thereof, including, forexample, di-block, tri-block, alternating, random, comb, star,dendritic, and graft copolymers (block copolymers are discussed in U.S.Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein byreference). In one embodiment, the hydrophobic-hydrophilic polymer is acopolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).Suitable such polymers include, but are not limited to, PEO-PPO diblockcopolymers, PPO-PEO-PPO triblock copolymers, PEO—PPO-PEO triblockcopolymers, alternating block copolymers of PEO-PPO, random copolymersof ethylene oxide and propylene oxide, and blends thereof. In someembodiments, the copolymers may be optionally substituted with hydroxysubstituents. Commercially available examples of PEO and PPO copolymersinclude the PLURONIC® brand of polymers available from BASF®. In oneembodiment, PLURONIC® F-127 is used. Other PLURONIC® polymers includePPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Othersuitable commercial polymers include, but are not limited to,SYNPERONICS® products available from UNIQEMA®.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, and 7Athrough 9B) includes electronic connections, for example, one or moreelectrical contacts configured to provide secure electrical contactbetween the sensor and associated electronics. In some embodiments, theelectrodes and membrane systems of the preferred embodiments arecoaxially formed, namely, the electrodes and/or membrane system allshare the same central axis. While not wishing to be bound by theory, itis believed that a coaxial design of the sensor enables a symmetricaldesign without a preferred bend radius. Namely, in contrast to prior artsensors comprising a substantially planar configuration that can sufferfrom regular bending about the plane of the sensor, the coaxial designof the preferred embodiments do not have a preferred bend radius andtherefore are not subject to regular bending about a particular plane(which can cause fatigue failures and the like). However, non-coaxialsensors can be implemented with the sensor system of the preferredembodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that a needle is able to insertthe sensor into the host and subsequently slide back over the sensor andrelease the sensor from the needle, without slots or other complexmulti-component designs, as described in detail in U.S. Publication No.US-2006-0063142-A1 and U.S. application Ser. No. 11/360,250 filed Feb.22, 2006 and entitled “ANALYTE SENSOR,” which are incorporated in theirentirety herein by reference.

Exemplary Continuous Sensor Configurations

In some embodiments, the sensor is an enzyme-based electrochemicalsensor, wherein the glucose-measuring working electrode 16 (e.g., FIGS.1A-1B) measures the hydrogen peroxide produced by the enzyme catalyzedreaction of glucose being detected and creates a measurable electroniccurrent (for example, detection of glucose utilizing glucose oxidaseproduces hydrogen peroxide (H₂O₂) as a by product, H₂O₂ reacts with thesurface of the working electrode producing two protons (2H⁺), twoelectrons (2e⁻) and one molecule of oxygen (O₂) which produces theelectronic current being detected, see FIG. 10 ), such as described inmore detail elsewhere herein and as is appreciated by one skilled in theart. Preferably, one or more potentiostat is employed to monitor theelectrochemical reaction at the electroactive surface of the workingelectrode(s). The potentiostat applies a constant potential to theworking electrode and its associated reference electrode to determinethe current produced at the working electrode. The current that isproduced at the working electrode (and flows through the circuitry tothe counter electrode) is substantially proportional to the amount ofH₂O₂ that diffuses to the working electrodes. The output signal istypically a raw data stream that is used to provide a useful value ofthe measured analyte concentration in a host to the patient or doctor,for example.

Some alternative analyte sensors that can benefit from the systems andmethods of the preferred embodiments include U.S. Pat. No. 5,711,861 toWard et al., U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No.6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S.Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis etal., U.S. Pat. No. 6,214,185 to Offenbacher et al., U.S. Pat. No.5,310,469 to Cunningham et al., and U.S. Pat. No. 5,683,562 to Shafferet al., U.S. Pat. No. 6,579,690 to Bonnecaze et al., U.S. Pat. No.6,484,046 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S.Pat. No. 6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 toMastrototaro et al, for example. All of the above patents areincorporated in their entirety herein by reference and are not inclusiveof all applicable analyte sensors; in general, it should be understoodthat the disclosed embodiments are applicable to a variety of analytesensor configurations.

Although some exemplary glucose sensor configurations are described indetail below, it should be understood that the systems and methodsdescribed herein can be applied to any device capable of continually orcontinuously detecting a concentration of analyte of interest andproviding an output signal that represents the concentration of thatanalyte, for example oxygen, lactose, hormones, cholesterol,medicaments, viruses, or the like.

FIG. 1A is a perspective view of an analyte sensor, including animplantable body with a sensing region including a membrane systemdisposed thereon. In the illustrated embodiment, the analyte sensor 10 aincludes a body 12 and a sensing region 14 including membrane andelectrode systems configured to measure the analyte. In this embodiment,the sensor 10 a is preferably wholly implanted into the subcutaneoustissue of a host, such as described in U.S. Publication No.US-2006-0015020-A1; U.S. Publication No. US-2005-0245799-A1; U.S.Publication No. US-2005-0192557-A1; U.S. Publication No.US-2004-0199059-A1; U.S. Publication No. US-2005-0027463-A1; and U.S.Pat. No. 6,001,067 issued Dec. 14, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS,” each of which are incorporated hereinby reference in their entirety.

The body 12 of the sensor 10 a can be formed from a variety ofmaterials, including metals, ceramics, plastics, or composites thereof.In one embodiment, the sensor is formed from thermoset molded around thesensor electronics. U.S. Publication No. US-2004-0199059-A1 disclosessuitable configurations for the body, and is incorporated by referencein its entirety.

In some embodiments, the sensing region 14 includes a glucose-measuringworking electrode 16, an optional auxiliary working electrode 18, areference electrode 20, and a counter electrode 24. Generally, thesensing region 14 includes means to measure two different signals, 1) afirst signal associated with glucose and non-glucose relatedelectroactive compounds having a first oxidation potential, wherein thefirst signal is measured at the glucose-measuring working electrodedisposed beneath an active enzymatic portion of a membrane system, and2) a second signal associated with the baseline and/or sensitivity ofthe glucose sensor. In some embodiments, wherein the second signalmeasures sensitivity, the signal is associated with at least onenon-glucose constant data point, for example, wherein the auxiliaryworking electrode 18 is configured to measure oxygen. In someembodiments, wherein the second signal measures baseline, the signal isassociated with non-glucose related electroactive compounds having thefirst oxidation potential, wherein the second signal is measured at anauxiliary working electrode 18 and is disposed beneath a non-enzymaticportion of the membrane system, such as described in more detailelsewhere herein.

Preferably, a membrane system (see FIG. 2A) is deposited over theelectroactive surfaces of the sensor 10 a and includes a plurality ofdomains or layers, such as described in more detail below, withreference to FIGS. 2A and 2B. In general, the membrane system may bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art. See U.S. Publication No.US-2006-0015020-A1.

The sensing region 14 comprises electroactive surfaces, which are incontact with an electrolyte phase (not shown), which is a free-flowingfluid phase disposed between the membrane system 22 and theelectroactive surfaces. In this embodiment, the counter electrode isprovided to balance the current generated by the species being measuredat the working electrode. In the case of glucose oxidase based analytesensors, the species being measured at the working electrode is H₂O₂.Glucose oxidase catalyzes the conversion of oxygen and glucose tohydrogen peroxide and gluconate according to the following reaction:

Glucose+O₂→Gluconate+H₂O₂

The change in H₂O₂ can be monitored to determine glucose concentrationbecause for each glucose molecule metabolized, there is a proportionalchange in the product H₂O₂ (see FIG. 10 ). Oxidation of H₂O₂ by theworking electrode is balanced by reduction of ambient oxygen, enzymegenerated H₂O₂, or other reducible species at the counter electrode. TheH₂O₂ produced from the glucose oxidase reaction further reacts at thesurface of the working electrode and produces two protons (2H⁺), twoelectrons (2e⁻), and one oxygen molecule (O₂). Preferably, one or morepotentiostats are employed to monitor the electrochemical reaction atthe electroactive surface of the working electrode(s). The potentiostatapplies a constant potential to the working electrode and its associatedreference electrode to determine the current produced at the workingelectrode. The current that is produced at the working electrode (andflows through the circuitry to the counter electrode) is substantiallyproportional to the amount of H₂O₂ that diffuses to the workingelectrodes. The output signal is typically a raw data stream that isused to provide a useful value of the measured analyte concentration ina host to the patient or doctor, for example.

FIG. 1B is a schematic view of an alternative exemplary embodiment of acontinuous analyte sensor 10 b, also referred to as an in-dwelling ortranscutaneous analyte sensor in some circumstances, particularlyillustrating the in vivo portion of the sensor. In this embodiment, thein vivo portion of the sensor 10 b is the portion adapted for insertionunder the host's skin, in a host's blood stream, or other biologicalsample, while an ex vivo portion of the sensor (not shown) is theportion that remains above the host's skin after sensor insertion andoperably connects to an electronics unit. In the illustrated embodiment,the analyte sensor 10 b is coaxial and includes three electrodes: aglucose-measuring working electrode 16, an optional auxiliary workingelectrode 18, and at least one additional electrode 20, which mayfunction as a counter and/or reference electrode, hereinafter referredto as the reference electrode 20. Generally, the sensor 10 b may includethe ability to measure two different signals, 1) a first signalassociated with glucose and non-glucose related electroactive compoundshaving a first oxidation potential, wherein the first signal is measuredat the glucose-measuring working electrode disposed beneath an activeenzymatic portion of a membrane system, and 2) a second signalassociated with the baseline and/or sensitivity of the glucose sensor,such as described in more detail above with reference to FIG. 1A.

One skilled in the art appreciates that the analyte sensor of FIG. 1Bcan have a variety of configurations. In one exemplary embodiment, thesensor is generally configured of a first working electrode, a secondworking electrode, and a reference electrode. In one exemplaryconfiguration, the first working electrode 16 is a central metal wire orplated non-conductive rod/filament/fiber and the second working andreference electrodes (20 and 18, respectively OR 18 and 20,respectively) are coiled around the first working electrode 16. Inanother exemplary configuration, the first working electrode is acentral wire, as depicted in FIG. 1B, the second working electrode iscoiled around the first working electrode, and the reference electrodeis disposed remotely from the sensor, as described herein. In anotherexemplary configuration, the first and second working electrodes (20 and18) are coiled around a supporting rod 16 of insulating material. Thereference electrode (not shown) can be disposed remotely from thesensor, as described herein, or disposed on the non-conductivesupporting rod 16. In still another exemplary configuration, the firstand second working electrodes (20 and 18) are coiled around a referenceelectrode 16 (not to scale).

Preferably, each electrode is formed from a fine wire, with a diameterin the range of 0.001 to 0.010 inches, for example, and may be formedfrom plated wire or bulk material, however the electrodes may bedeposited on a substrate or other known configurations as is appreciatedby one skilled in the art.

In one embodiment, the glucose-measuring working electrode 16 comprisesa wire formed from a conductive material, such as platinum, palladium,graphite, gold, carbon, conductive polymer, or the like. Alternatively,the glucose-measuring working electrode 16 can be formed of anon-conductive fiber or rod that is plated with a conductive material.The glucose-measuring working electrode 16 is configured and arranged tomeasure the concentration of glucose. The glucose-measuring workingelectrode 16 is covered with an insulating material, for example anon-conductive polymer. Dip-coating, spray-coating, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode, for example. In one preferred embodiment, theinsulating material comprises Parylene, which can be an advantageousconformal coating for its strength, lubricity, and electrical insulationproperties, however, a variety of other insulating materials can beused, for example, fluorinated polymers, polyethyleneterephthalate,polyurethane, polyimide, or the like.

In this embodiment, the auxiliary working electrode 18 comprises a wireformed from a conductive material, such as described with reference tothe glucose-measuring working electrode 16 above. Preferably, thereference electrode 20, which may function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, Silver/Silver chloride, or the like.

Preferably, the electrodes are juxtapositioned and/or twisted with oraround each other; however other configurations are also possible. Inone example, the auxiliary working electrode 18 and reference electrode20 may be helically wound around the glucose-measuring working electrode16 as illustrated in FIG. 1B. Alternatively, the auxiliary workingelectrode 18 and reference electrode 20 may be formed as a double helixaround a length of the glucose-measuring working electrode 16. In someembodiments, the working electrode, auxiliary working electrode andreference electrodes may be formed as a triple helix. The assembly ofwires may then be optionally coated together with an insulatingmaterial, similar to that described above, in order to provide aninsulating attachment. Some portion of the coated assembly structure isthen stripped, for example using an excimer laser, chemical etching, orthe like, to expose the necessary electroactive surfaces. In somealternative embodiments, additional electrodes may be included withinthe assembly, for example, a three-electrode system (including separatereference and counter electrodes) as is appreciated by one skilled inthe art.

FIGS. 2A and 2B are schematic views membrane systems in some embodimentsthat may be disposed over the electroactive surfaces of an analytesensors of FIGS. 1A and 1B, respectively, wherein the membrane systemincludes one or more of the following domains: a resistance domain 30,an enzyme domain 28, an optional interference domain 26, and anelectrolyte domain 24, such as described in more detail below. However,it is understood that the membrane system 22 can be modified for use inother sensors, by including only one or more of the domains, additionaldomains not recited above, or for other sensor configurations. Forexample, the interference domain can be removed when other methods forremoving interferants are utilized, such as an auxiliary electrode formeasuring and subtracting out signal due to interferants. As anotherexample, an “oxygen antenna domain” composed of a material that hashigher oxygen solubility than aqueous media so that it concentratesoxygen from the biological fluid surrounding the biointerface membranecan be added. The oxygen antenna domain can then act as an oxygen sourceduring times of minimal oxygen availability and has the capacity toprovide on demand a higher rate of oxygen delivery to facilitate oxygentransport to the membrane. This enhances function in the enzyme reactiondomain and at the counter electrode surface when glucose conversion tohydrogen peroxide in the enzyme domain consumes oxygen from thesurrounding domains. Thus, this ability of the oxygen antenna domain toapply a higher flux of oxygen to critical domains when needed improvesoverall sensor function.

In some embodiments, the membrane system generally provides one or moreof the following functions: 1) protection of the exposed electrodesurface from the biological environment, 2) diffusion resistance(limitation) of the analyte, 3) a catalyst for enabling an enzymaticreaction, 4) optionally limitation or blocking of interfering species,and 5) hydrophilicity at the electrochemically reactive surfaces of thesensor interface, such as described in U.S. Publication No.US-2005-0245799-A1. In some embodiments, the membrane systemadditionally includes a cell disruptive domain, a cell impermeabledomain, and/or an oxygen domain (not shown), such as described in moredetail in U.S. Publication No. US-2005-0245799-A1. However, it isunderstood that a membrane system modified for other sensors, forexample, by including fewer or additional domains is within the scope ofthe preferred embodiments.

One aspect of the preferred embodiments provides for a sensor (fortranscutaneous, wholly implantable, or intravascular short-term orlong-term use) having integrally formed parts, such as but not limitedto a plurality of electrodes, a membrane system and an enzyme. Forexample, the parts may be coaxial, juxtapositioned, helical, bundledand/or twisted, plated and/or deposited thereon, extruded, molded, heldtogether by another component, and the like. In another example, thecomponents of the electrode system are integrally formed, (e.g., withoutadditional support, such as a supporting substrate), such thatsubstantially all parts of the system provide essential functions of thesensor (e.g., the sensing mechanism or “in vivo” portion). In a furtherexample, a first electrode can be integrally formed directly on a secondelectrode (e.g., electrically isolated by an insulator), such as byvapor deposition of a conductive electrode material, screen printing aconductive electrode ink or twisting two electrode wires together in acoiled structure.

Some embodiments provide an analyte sensor that is configured forinsertion into a host and for measuring an analyte in the host, whereinthe sensor includes a first working electrode disposed beneath an activeenzymatic portion of a membrane (e.g., membrane system) on the sensorand a second working electrode disposed beneath an inactive- ornon-enzymatic portion of the membrane on the sensor. In theseembodiments, the first and second working electrodes integrally form atleast a portion of the sensor.

Exemplary Sensor Configurations

FIG. 1B is a schematic view of a sensor in one embodiment. In somepreferred embodiments, the sensor is configured to be integrally formedand coaxial. In this exemplary embodiment, one or more electrodes arehelically wound around a central core, all of which share axis A-A. Thecentral core 16 can be an electrode (e.g., a wire or metal-platedinsulator) or a support made of insulating material. The coiledelectrodes 18, 20 are made of conductive material (e.g., plated wire,metal-plated polymer filaments, bulk metal wires, etc.) that ishelically wound or twisted about the core 16. Generally, at least theworking electrodes are coated with an insulator I of non-conductive ordielectric material.

One skilled in the art will recognize that various electrodecombinations are possible. For example, in one embodiment, the core 16is a first working electrode and can be substantially straight. One ofthe coiled electrodes (18 or 20) is a second working electrode and theremaining coiled electrode is a reference or counter electrode. In afurther embodiment, the reference electrode can be disposed remotelyfrom the sensor, such as on the host's skin or on the exterior of thesensor, for example. Although this exemplary embodiment illustrates anintegrally formed coaxial sensor, one skilled in the art appreciates avariety of alternative configurations. In one exemplary embodiment, thearrangement of electrodes is reversed, wherein the first workingelectrode is helically wound around the second working electrode core16. In another exemplary embodiment, the reference electrode can formthe central core 16 with the first and second working electrodes coiledthere around. In some exemplary embodiments, the sensor can haveadditional working, reference and/or counter electrodes, depending uponthe sensor's purpose. Generally, one or more of the electrode wires arecoated with an insulating material, to prevent direct contact betweenthe electrodes. Generally, a portion of the insulating material can beremoved (e.g., etched, scraped or grit-blasted away) to expose anelectroactive surface of the electrode. An enzyme solution can beapplied to the exposed electroactive surface, as described herein.

The electrodes each have first and second ends. The electrodes can be ofany geometric solid shape, such as but not limited to a cylinder havinga circular or oval cross-section, a rectangle (e.g., extrudedrectangle), a triangle (e.g., extruded triangle), an X-cross section, aY-cross section, flower petal-cross sections, star-cross sections,melt-blown fibers loaded with conductive material (e.g., conductivepolymers) and the like. The first ends (e.g., an in vivo portion, “frontend”) of the electrodes are configured for insertion in the host and thesecond ends (e.g., an ex vivo portion, “back end”) are configured forelectrical connection to sensor electronics. In some embodiments, thesensor includes sensor electronics that collect data from the sensor andprovide the data to the host in various ways. Sensor electronics arediscussed in detail elsewhere herein.

FIGS. 7A1 and 7A2 are schematics of an analyte sensor in anotherembodiment. FIG. 7A1 is a side view and FIG. 7A2 is a side-cutaway view.In some preferred embodiments, the sensor is configured to be integrallyformed and coaxial, with an optional stepped end. In this exemplaryembodiment, the sensor includes a plurality of electrodes E1, E2, E3 toEn, wherein n equals any number of electrode layers. Layers ofinsulating material I (e.g., non-conductive material) separate theelectrode layers. All of the electrode and insulating material layersshare axis A-A. The layers can be applied by any technique known in theart, such as but not limited to spraying, dipping, spraying, etc. Forexample, a bulk metal wire electrode E1 can be dipped into a solution ofinsulating polymer that is vulcanized to form a layer of non-conductive,electrically insulating material I. A second electrode E2 can be plated(e.g., by electroplating or other plating technique used in the art) onthe first insulating layer, followed by application of a secondinsulating layer I applied in the same manner as the first layer.Additional electrode layers (e.g., E3 to En) and insulating layers canbe added to the construct, to create the desired number of electrodesand insulating layers. As an example, multiple sensors can be formedfrom a long wire (with insulating and electrode layers applied) that canbe cut to yield a plurality of sensors of the desired length. After thesensor has been cut to size, it can be polished or otherwise treated toprepare the electrodes for use. In some embodiments, the variouselectrode and/or insulator layers can be applied by dipping, spraying,printing, vapor deposition, plating, spin coating or any other methodknown in the art. Although this exemplary embodiment illustrates anintegrally formed coaxial sensor, one skilled in the art appreciates avariety of alternative configurations. For example, in some embodiments,the sensor can have two, three, four or more electrodes separated byinsulating material I. In another embodiment, the analyte sensor has twoor more electrodes, such as but not limited to a first workingelectrode, an auxiliary working electrode, a reference electrode and/orcounter electrode. FIG. 7B is a schematic view of an integrally formed,coaxial sensor in another embodiment. In this exemplary embodiment, acoiled first electrode E1 is manufactured from an electricallyconductive tube or cylinder, such as but not limited to a silverHypotube. A portion of the Hypotube is trimmed or carved into a helix orcoil 702. A second electrode E2 that is sized to fit (e.g., with minimaltolerance) within the first electrode E1 mates (e.g., slides into) withthe first electrode E1, to form the sensor. In general, the surfaces ofthe electrodes are coated with an insulator, to prevent direct contactbetween the electrodes. As described herein, portion of the insulatorcan be stripped away to expose the electroactive surfaces. Although thisexemplary embodiment illustrates one configuration of a coaxial,integrally formed sensor, one skilled in the art appreciates a varietyof alternative configurations. For example, in some embodiments, thefirst electrode E1 is a reference or auxiliary electrode, and the secondelectrode E2 is a working electrode. However, the first electrode E1 canbe a working electrode and the second electrode E2 can be a reference orauxiliary electrode. In some embodiments, additional electrodes areapplied to the construct (e.g., after E2 is inserted into E1). Oneadvantage of this configuration is that the silver Hypotube can be cutto increase or decrease the flexibility of the sensor. For example, thespiral cut can space the coils farther apart to increase the sensor'sflexibility. Another example of this configuration is that it is easierto construct the sensor in this manner, rather than winding oneelectrode around another (e.g., as is done for the embodiment shown inFIG. 1B).

FIGS. 7C to 7E are schematics of three embodiments of bundled analytesensors. In these embodiments, of the sensors are configured to beintegrally formed sensors, wherein a plurality (E1, E2, E3, to En) ofelectrodes are bundled, coiled or twisted to form a portion of thesensor. In some embodiments, the electrodes can be twisted or helicallycoiled to form a coaxial portion of the sensor, which share the sameaxis. In one embodiment, the first and second working electrodes aretwisted or helically wound together, to form at least a portion of thesensor (e.g., a glucose sensor). For example, the electrodes can betwisted in a double helix. In some embodiments, additional electrodesare provided and twisted, coiled or wound with the first and secondelectrodes to form a larger super helix, such as a triple helix, aquadruple helix, or the like. For example, three wires (E1, E2, and E3)can be twisted to form a triple helix. In still other embodiments, atleast one reference electrode can be disposed remotely from the workingelectrodes, as described elsewhere herein. In some embodiments, the tipof the sensor can be cut at an angle (90° or other angle) to expose theelectrode tips to varying extents, as described herein.

FIG. 7C is a schematic of an exemplary embodiment of a sensor havingthree bundled electrodes E1, E2, and E3. In some preferred embodimentsof the sensor, two or all of the electrodes can be identical.Alternatively, the electrodes can be non-identical. For example, thesensor can have a glucose-sensing electrode, an oxygen-sensing electrodeand a reference electrode. Although this exemplary embodimentillustrates a bundled sensor, one skilled in the art appreciates avariety of alternative sensor configurations. For example, only twoelectrodes can be used or more than three electrodes can be used. Inanother example, holding one end of the bundled wires in a clamp andtwisting the other end of the wires, to form a cable-like structure, cancoil the electrodes together. Such a coiled structure can hold theelectrodes together without additional structure (e.g., bound by a wireor coating). In another example, non-coiled electrodes can be bundledand held together with a wire or fiber coiled there around, or byapplying a coating of insulating material to the electrode bundle. Instill another example, the reference electrode can be disposed remotelyfrom the working electrodes, as described elsewhere herein.

FIG. 7D is a schematic view of a sensor in one embodiment. In somepreferred embodiments, the sensor is designed to be integrally formedand bundled and/or coaxial. In this exemplary embodiment, the sensorincludes seven electrodes, wherein three electrodes of a first type(e.g., 3×E1) and three electrodes of a second type (e.g., 3×E2) arebundled around one electrode of a third type (e.g., E3). Those skilledin the art appreciate a variety of configurations possible with thisembodiment. For example, the different types of electrodes can bealternated or not alternated. For example, in FIG. 7D, the two types ofelectrodes are alternately disposed around E3. However, the two types ofelectrodes can be grouped around the central structure. As describedherein, some or all of the electrodes can be coated with a layer ofinsulating material, to prevent direct contact between the electrodes.The electrodes can be coiled together, as in a cable, or held togetherby a wire or fiber wrapping or a coating of insulating material. Thesensor can be cut, to expose the electroactive surfaces of theelectrodes, or portions of the insulating material coating can bestripped away, as described elsewhere herein. In another example, thesensor can include additional (or fewer) electrodes. In one exemplaryembodiment, the E1 and E2 electrodes are bundled around a non-conductivecore (e.g., instead of electrode E3), such as an insulated fiber. Inanother embodiment, different numbers of E1, E2, and E3 electrodes canbe used (e.g., two E1 electrodes, two E2 electrodes, and three E3electrodes). In another embodiment, additional electrode type can beincluded in the sensor (e.g., an electrode of type E4, E5 or E6, etc.).In still another exemplary embodiment, three glucose-detectingelectrodes (e.g., E1) and three reference electrodes (e.g., E2) arebundled and (optionally) coiled around a central auxiliary workingelectrode (e.g., E3).

FIG. 7E is a schematic of a sensor in another embodiment. In thisexemplary embodiment of an integrally formed sensor, two pairs ofelectrodes (e.g., 2×E1 and 2×E2) are bundled around a core of insulatingmaterial I. Fibers or strands of insulating material I also separate theelectrodes from each other. Although this exemplary embodimentillustrates an integrally formed sensor, one skilled in the artappreciates a variety of alternative configurations. For example, thepair of E1 electrodes can be working electrodes and the pair of E2electrodes can be reference and/or auxiliary electrodes. In oneexemplary embodiment, the E1 electrodes are both glucose-detectingelectrodes, a first E2 electrode is a reference electrode and a secondE2 electrode is an auxiliary electrode. In another exemplary embodiment,one E1 electrode includes active GOx and measures a glucose-relatedsignal; the other E1 electrode lacks active GOx and measures anon-glucose-related signal, and the E2 electrodes are referenceelectrodes. In yet another exemplary embodiment, one E1 electrodedetects glucose and the other E1 electrode detects urea, and both E2electrodes are reference electrodes. One skilled in the art ofelectrochemical sensors will recognized that the size of the variouselectrodes can be varied, depending upon their purpose and the currentand/or electrical potential used. Electrode size and insulating materialsize/shape are not constrained by their depiction of relative size inthe Figures, which are schematic schematics intended for onlyillustrative purposes.

FIG. 7F is a schematic view of a cross-section of an integrally formedsensor in another embodiment. In some preferred embodiments, the sensoris configured to be bifunctional. In this exemplary embodiment, thesensor includes two working electrodes E1/E2 separated by either areference electrode R or an insulating material I. The electrodes E1, E2and optionally the reference electrode R are conductive and support thesensor's shape. In addition, the reference electrode R (or theinsulating material I) can act as a diffusion barrier (D, describedherein) between the working electrodes E1, E2 and support the sensor'sstructure. Although this exemplary embodiment illustrates oneconfiguration of an integrally formed sensor having bifunctionalcomponents, one skilled in the art appreciates a variety of alternativeconfigurations. Namely, FIG. 7F is not to scale and the workingelectrodes E1, E2 can be relatively larger or smaller in scale, withregard to the reference electrode/insulator R/I separating them. Forexample, in one embodiment, the working electrodes E1, E2 are separatedby a reference electrode that has at least 6-times the surface area ofthe working electrodes, combined. While the working electrodes E1, E2and reference electrode/insulator R/I are shown and semi-circles and arectangle, respectively, one skilled in the art recognizes that thesecomponents can take on any geometry know in the art, such as but notlimited to rectangles, cubes, cylinders, cones, and the like.

FIG. 7G is a schematic view of a sensor in yet another embodiment. Insome preferred embodiments, the sensor is configured to be integrallyformed with a diffusion barrier D, as described herein. In thisexemplary embodiment, the working electrodes E1, E2 (or one workingelectrode and one counter electrode) are integrally formed on asubstantially larger reference electrode R or an insulator I thatsubstantially prevents diffusion of analyte or other species from oneworking electrode to another working electrode (e.g., from the enzymaticelectrode (e.g., coated with active enzyme) to the non-enzymaticelectrode (e.g., no enzyme or inactive enzyme)). Although this exemplaryembodiment illustrates an integrally formed sensor having a diffusionbarrier, one skilled in the art appreciates a variety of alternativeconfigurations. For example, in one embodiment, the reference electrodeis designed to include an exposed electroactive surface area that is atleast equal to, greater than, or more than about 2, 3, 4, 5, 6, 7, 8, 9,10 or more times greater than the surface area of the working electrodes(e.g., combined). In other embodiments, the surface of the referenceelectrode is about 6 (e.g., about 6 to 20) or more times greater thanthe working electrodes. In some embodiments, each working electrodedetects a separate analyte (e.g., glucose, oxygen, uric acid, nitrogen,pH, and the like). In other embodiments, one of the working electrodesis a counter electrode. In still another exemplary embodiment, an enzymesolution containing active GOx is applied to the E1 electroactivesurface, while an enzyme solution containing inactive GOx (or no GOx atall) is applied to the E2 electroactive surface. As described herein,this configuration allows the measurement of two signals. Electrode E1measures both a signal related to glucose concentration and a signalthat is not related to glucose concentration. Electrode E2 measures asignal that is not related to glucose concentration. The sensorelectronics, as described herein, can use these data to calculateglucose concentration without signal due to non-glucose-relatedcontributions.

FIG. 7H is a schematic view of a sensor in another embodiment. In somepreferred embodiments, the sensor is configured of a geometric solid(e.g., cylindrical) reference electrode R having two or more workingelectrodes E1, E2 to En disposed within two or more grooves or channelscarved in the sides of the reference electrode R (parallel to the axisof the reference electrode R). The grooves are sized such that theelectrodes E1, E2 can snuggly fit therein. Additionally, the depth ofthe grooves can be configured that the electrode placed therein isexternally exposed to a greater or lesser degree. For example, theopening to the groove may be wider or narrower. In some embodiments, aportion of an electrode protrudes from the groove in which the electrodehas been disposed. In some embodiments, an insulator (e.g., I) takes theplace of a reference electrode (which can be disposed elsewhere, suchremotely as described in more detail elsewhere herein). The referenceelectrode/insulator R/I can take any geometric structure known in theart, such as but not limited to cylinders, rectangles, cones, and thelike. Similarly, the relative sizes of the working electrodes E1, E2 andthe reference electrode/insulator R/I can be varied to achieve a desiredsignal level, to enable the use of the desired voltage (e.g., to biasthe sensor), and the like, as described herein.

In one exemplary embodiment, a diffusion barrier D (described in greaterdetail below) separates the working electrodes. The diffusion barriercan be spatial, physical, or temporal. For example, the distance aroundthe reference electrode (e.g., from the first working electrode E1 tothe second working electrode E2, around a portion of the circumferenceof the reference electrode R) acts as a spatial diffusion barrier. Inone exemplary embodiment, the working electrodes are coated with a layerof insulating material I (e.g., non-conductive material or dielectric)to prevent direct contact between the working electrodes E1, E2 and thereference electrode R. A portion of the insulator I on an exteriorsurface of each working electrode is etched away, to expose theelectrode's electroactive surface. In some embodiments, an enzymesolution (e.g., containing active GOx) is applied to the electroactivesurfaces of both electrodes, and dried. Thereafter, the enzyme appliedto one of the electroactive surfaces is inactivated. As is known in theart, enzymes can be inactivated by a variety of means, such as heat,treatment with inactivating (e.g., denaturing) solvents, proteolysis,laser irradiation or UV irradiation (e.g., at 254-320 nm). For example,the enzyme coating one of the electroactive surfaces can be inactivatedby masking one of the electroactive surfaces/electrodes (e.g., E1,temporarily covered with a UV-blocking material); irradiating the sensorwith UV light (e.g., 254-320 nm; a wavelength that inactivates theenzyme, such as by cross-linking amino acid residues) and removing themask. Accordingly, the GOx on E2 is inactivated by the UV treatment, butthe E1 GOx is still active due to the protective mask. In otherembodiments, an enzyme solution containing active enzyme is applied to afirst electroactive surface (e.g., E1) and an enzyme solution containingeither inactivated enzyme or no enzyme is applied to the secondelectroactive surface (e.g., E2). Accordingly, the enzyme-coated firstelectroactive surface (e.g., E1) detects analyte-related signal andnon-analyte-related signal; while the second electroactive surface(e.g., E2), which lacks active enzyme, detects non-analyte-relatedsignal. As described herein, the sensor electronics can use the datacollected from the two working electrodes to calculate the analyte-onlysignal.

Although this exemplary embodiment illustrates one embodiment of anintegrally-formed sensor having a diffusion barrier D, one skilled inthe art appreciates a variety of alternative configurations, such as butnot limited to the embodiment shown in FIG. 7I. In this exemplaryembodiment, the reference electrode is formed of at least two adjacentpieces shaped such that the working electrodes fill at least some spacebetween them. The at least two pieces can be any shape known in the art,as described herein. In some embodiments, the at least two pieces aresymmetrical and/or mirror images of each other, but one skilled in theart will recognize that this is not a requirement. In variousembodiments, an insulating material can be coated on the workingelectrodes and/or the reference electrode(s) to prevent contact therebetween. As described elsewhere herein, the working electrodes candetect the same analyte or separate analytes, or one of the workingelectrodes may act as a counter electrode (e.g., auxiliary electrode).Although this exemplary embodiment illustrates one example of a sensorhaving a reference electrode R that is formed of at least two piecesshaped such that the working electrodes fill at least some space betweenthe pieces, one skilled in the art appreciates that a variety of sensorconfigurations are possible. For example, the reference electrode can beformed of three or more pieces. In other example, the sensor can beconfigured with more than two working electrodes (e.g., 3, 4, or 5working electrodes, or more).

FIG. 7J is a schematic view of an integrally formed sensor in yetanother embodiment. In this exemplary embodiment, the referenceelectrode R is formed in any desired extruded geometry, such as anapproximate X-shape. Two or more working electrodes E1, E2 are disposedon substantially opposing sides of the reference electrode, with adiffusion barrier D between them. In this embodiment, the diffusionbarrier is a physical diffusion barrier, namely the distance between thetwo working electrodes (e.g., around the reference electrode). In someembodiments, the electrodes are bundled and held together by a wrappingof wire or fiber. In other embodiments, the electrodes are twistedaround the lengthwise axis of the extruded X-shaped reference electrode,to form a coaxial sensor. Although this exemplary embodiment illustratesan integrally formed sensor, one skilled in the art appreciates avariety of alternative configurations. For example, furthering someembodiments, three or four working electrodes can be disposed around thereference electrode (e.g., in the indentations between the legs/arms ofthe X-shaped electrode). In other embodiments, the reference electrodecan be Y-shapes, star-shaped, flower-shaped, scalloped, or any otherconvenient shape with multiple substantially isolated sides. In someembodiments, an insulating material I takes the place of the referenceelectrode of FIG. 7J, which is remotely located. In an alternativeembodiment, a working electrode is replaced with a counter electrode. Asdescribed elsewhere herein, the sensor components are bifunctional.Namely, the electrodes and reference electrode provide electricalconduction and the sensor's structure. The reference electrode (orinsulating material) provides a physical diffusion barrier D. Inaddition to providing shape to the sensor, the insulating material actsas insulator by preventing direct electrical contact between theelectrodes. Similarly, the materials selected to construct the sensordetermine the sensor's flexibility. As described elsewhere, activeenzyme is applied to the electroactive surface of at least one workingelectrode (e.g., E1). In some embodiments, no enzyme (or inactivatedenzyme) is applied to the electroactive surface of a second workingelectrode (e.g., E2). In an alternative embodiment, a second enzyme isapplied to the second working electrode (e.g., E2) such that the sensorcan measure the signals of two different analytes (e.g., glucose andaureate or oxygen). FIG. 7K is a schematic of a sensor in anotherembodiment. In some preferred embodiments, the sensor is configured tobe integrally formed of two working electrodes. In this exemplaryembodiment, the sensor includes two electrodes E1, E2 (e.g., metalwires), wherein each electrode is coated with a non-conductive materialI (e.g., and insulator). As is shown in FIG. 7K, the first workingelectrode E1 formed within the insulator I leaving space for an enzyme.For example, an enzyme solution 702 (e.g., GOx for detecting glucose) isdisposed within the space 701. In contrast, the second working electrodeE2 extends substantially flush with the insulator I. A membrane system703 coats the electrodes. A diffusion barrier D separates the workingelectrodes. In some embodiments, the first and second electrodes areseparated by a distance D that substantially prevents diffusion of H₂O₂from the first electrode (e.g., with active enzyme) to the secondelectrode (e.g., without active enzyme). Although this exemplaryembodiment illustrates one integrally formed sensor, one skilled in theart appreciates a variety of alternative configurations. For example,the use of more than two working electrodes and wrapping the constructwith a reference electrode wire R or disposing the reference electroderemotely from the sensor.

FIG. 7L is a schematic of a sensor in one embodiment. In some preferredembodiments, the sensor is designed to be integrally formed. In thisexemplary embodiment, two electrodes E1, E2 are embedded within aninsulator I. The sensor can be formed by embedding conductive wireswithin a dielectric, curing the dielectric and then cutting sensors ofthe desired length. The cut end provides the exposed electroactiveelectrode surfaces and can be polished or otherwise treated. Althoughthis exemplary embodiment illustrates one integrally formed sensor, oneskilled in the art appreciates a variety of alternative configurations.For example, additional electrode wires can be embedded in thedielectric material. In another example, a reference electrode (e.g.,wire or cylinder) can be coiled or wrapped around the sensor (e.g., onthe surface of the insulator). Alternatively, as described elsewhereherein, the reference electrode can be disposed remotely from theworking electrodes E1, E2, such as on the host's skin or on anotherportion of the sensor. One advantage of this configuration is that it isrelatively simple to embed electrode wires in a long cylinder ofinsulating material and then cut the sensors to any desired size and/orshape.

FIG. 7M is a schematic cross-sectional view of a sensor having multipleworking and reference electrodes, in one embodiment. In some preferredembodiments, the sensor is integrally formed. In this exemplaryembodiment, the sensor includes a plurality of working electrodes (e.g.,E1, E2, E3) that are layered with a plurality of reference electrodes(e.g., R1, R2, Rn). In some embodiments, the working electrodes arecoated with an insulating material to prevent direct contact withadjacent reference electrodes. In some embodiments, the referenceelectrodes are also coated with insulative material. In someembodiments, layers of insulating material separate the layers. In someembodiments, at least one of the working electrodes is a counterelectrode. As described herein, in some embodiments, electroactivesurfaces are exposed on one or more electrodes, such as by strippingaway a portion of an insulating coating, such as on the sides of thesensor. In other embodiments, an extended electrode structure (e.g., along sandwich of electrode layers) that is cut to the desired length,and the cut end includes the exposed electroactive surfaces of theelectrodes. An enzyme layer can be applied to one or more of theelectroactive surfaces, as described herein. Depending upon the desiredsensor function, the working electrodes can be configured to detect thesame analyte (e.g., all electroactive surfaces coated with GOx glucose)or different analytes (e.g., one working electrode detects glucose,another detects oxygen and the third detects ureate), as describedherein. Although this exemplary embodiment illustrates a sensor having aplurality of working and reference electrodes, one skilled in the artappreciates a variety of alternative configurations. For example, insome embodiments, the electrodes can be of various sizes, depending upontheir purpose. For example, in one sensor, it may be preferred to use a3 mm oxygen electrode, a 10 mm glucose electrode and a 4 mm counterelectrode, all separated by reference electrodes. In another embodiment,each reference electrode can be functionally paired with a workingelectrode. For example, the electrodes can be pulsed on and off, suchthat a first reference electrode R1 is active only when the firstworking electrode E1 is active, and a second reference electrode R2 isactive only when the second working electrode E2 is active. In anotherembodiment, a flat sensor (e.g., disk-shaped) can be manufactured bysandwiching reference electrodes between working electrodes, cutting thesandwich into a cylinder, and the cutting the cylinder cross-wise(perpendicularly or at an angle) into disks.

FIG. 7N is a schematic cross-sectional view of the manufacture of anintegrally formed sensor, in one embodiment. In some preferredembodiments, at least two working electrodes (E1, E2) and optionally areference electrode R are embedded in a quantity 704 of insulatingmaterial I. The working electrodes are separated by a diffusion barrierD. After the insulator has been cured (e.g., vulcanized or solidified)the structure is shaped (e.g., carved, scraped or cut etc.) to the finalsensor shape 705, such that excess insulation material is removed. Insome embodiments, multiple sensors can be formed as an extendedstructure of electrode wires embedded in insulator, which issubsequently cut to the desired length, wherein the exposed electrodeends (e.g., at the cut surface) become the electroactive surfaces of theelectrodes. In other embodiments, portions of the insulator adjacent tothe electrodes (e.g., windows) can be removed (e.g., by cutting orscraping, etc.) to expose the electroactive surfaces. Depending upon thesensor's configuration and purpose, an enzyme solution can be applied toone or more of the electroactive surfaces, as described elsewhereherein. Although this exemplary embodiment illustrates one technique ofmanufacturing a sensor having insulation-embedded electrodes, oneskilled in the art appreciates a variety of alternative configurations.For example, a diffusion barrier D, can comprise both the referenceelectrode R and the insulating material I, or only the referenceelectrode. In another example, windows exposing the electroactivesurfaces can be formed adjacent to each other (e.g., on the same side ofthe reference electrode) or on opposite sides of the referenceelectrode. Still, in other embodiments, more working or referenceelectrodes can be included, and the working and reference electrodes canbe of relatively larger or smaller size, depending upon the sensor'sconfiguration and operating requirements (e.g., voltage and/or currentrequirements).

FIGS. 8A and 8B are schematic views of a sensor in yet anotherembodiment. FIG. 8A is a view of the cross-section and side of an invivo portion of the sensor. FIG. 8B is a side view of the ex vivoportion of the sensor (e.g., the portion that is connected to the sensorelectronics, as described elsewhere herein). Namely, two workingelectrodes E1, E2 that are coated with insulator I and then disposed onsubstantially opposing sides of a reference electrode R, such as asilver or silver/silver chloride electrode (see FIG. 8A). The workingelectrodes are separated by a diffusion barrier D that can include aphysical barrier (provided by the reference electrode and/or theinsulating material coatings), a spatial barrier (provided by staggeringthe electroactive surfaces of the working electrodes), or a temporalbarrier (provided by oscillating the potentials between the electrodes).In some embodiments, the reference electrode R has a surface area atleast 6-times the surface area of the working electrodes. Additionally,the reference electrode substantially can act as a spatial diffusionbarrier between the working electrodes due to its larger size (e.g., thedistance across the reference electrode, from one working electrode toanother).

The electrodes can be held in position by wrapping with wire or anon-conductive fiber, a non-conductive sheath, a biointerface membranecoating, or the like. The electroactive surfaces of the workingelectrodes are exposed. In some embodiments, the end of the sensor iscut off, to expose the ends of the wires. In other embodiments, the endsof the wires are coated with insulating material; and the electroactivesurfaces are exposed by removing a portion of the insulating material(e.g., a window 802 cut into the side of the insulation coating theelectrode). In some embodiments, the windows exposing the electroactivesurfaces of the electrodes can be staggered (e.g., spaced such that oneor more electrodes extends beyond the other one or more electrodes),symmetrically arranged or rotated to any degree; for example, tosubstantially prevent diffusion of electroactive species from oneworking electrode (e.g., 802 a) to the other working electrode (e.g.,802 b), as will be discussed in greater detail elsewhere herein. Invarious embodiments, the reference electrode is not coated with anonconductive material. The reference electrode can have a surface areathat is at least 6 times the surface area of the exposed workingelectrode electroactive surfaces. In some embodiments, the referenceelectrode R surface area is 7-10 times (or larger) than the surface areaof the working electrode electroactive surfaces. In still otherembodiments, the reference electrode can be only 1-5 times the surfacearea of working electrode electroactive surfaces (e.g., (E1+E2)×1=R or(E1+E2)×2=R, etc.).

The ex vivo end of the sensor is connected to the sensor electronics(not shown) by electrical connectors 804 a, 804 b, 804 c. In someembodiments, the ex vivo end of the sensor is stepped. For example, theex vivo end of the reference electrode R terminates within electricalconnector 804 a. The ex vivo end of the first working electrode E1 isexposed (e.g., nonconductive material removed therefrom) and terminatesa small distance past the reference electrode R, within electricalconnector 804 b. Similarly, the ex vivo end of the second workingelectrode E2 is exposed (e.g., nonconductive material removed therefrom)and terminates a small distance past the termination of the firstworking electrode E1, within electrical connector 804 c.

Although this exemplary embodiment illustrates one configuration of anintegrally formed sensor, one skilled in the art appreciates a varietyof alternative configurations. For example, in some embodiments, aportion of the in vivo portion of the sensor can be twisted and/orstepped. More working, reference, and/or counter electrodes, as well asinsulators, can be included. The electrodes can be of relatively largeror smaller size, depending upon the sensor's intended function. In someembodiments, the electroactive surfaces can be staggered. In still otherembodiments, the reference electrode can be disposed remotely from thesensor, as described elsewhere herein. For example, the referenceelectrode shown in FIG. 8A can be replaced with a non-conductive supportand the reference electrode disposed on the host's skin.

With reference to the ex vivo portion of the sensor, one skilled in theart appreciates additional alternative configurations. For example, inone embodiment, a portion of the ex vivo portion of the sensor can betwisted or coiled. In some embodiments, the working and referenceelectrodes can be of various lengths and configurations not shown inFIG. 8B. For example, the reference electrode R can be the longest(e.g., connect to electrical contact 804 c) and the first second workingelectrode E2 can be the shortest (e.g., connect to electrical contact804 a). In other embodiments, the first working electrode E1 may beeither the longest electrode (e.g., connect to electrical contact 804 c)or the shortest electrode (e.g., connect to electrical contact 804 a).

FIG. 9A is a schematic view that illustrates yet another exemplaryembodiment of an integrally formed analyte sensor. Namely, two workingelectrodes E1, E2 are bundled together and substantially encircled witha cylindrical silver or silver/silver chloride reference electrode R (orthe like). The reference electrode can be crimped at a location 902, toprevent movement of the working electrodes E1, E2 within the referenceelectrode R cylinder. In alternative embodiments, a reference electrodecan be rolled or coiled around the working electrodes E1, E2, to formthe reference electrode R. Preferably, the working electrodes are atleast partially insulated as described in more detail elsewhere herein;such as by coating with a non-conductive material, such as but notlimited to Parylene. One skilled in the art appreciates that a varietyof alternative configurations are possible.

FIG. 9B illustrates another embodiment of an integrally formed analytesensor. Namely, two working electrodes E1, E2 are bundled together witha silver or silver/silver chloride wire reference electrode R coiledthere around. The reference electrode can be coiled tightly, to preventmovement of the working electrodes E1, E2 within the reference electrodeR coil.

Referring again to FIGS. 9A to 9B, near the tip of the in vivo portionof the sensor, windows 904 a and 904 b are formed on the workingelectrodes E1, E2. Portions of the non-conductive material (e.g.,insulator) coating each electrode is removed to form windows 904 a and904 b. The electroactive surfaces of the electrodes are exposed viawindows 904 a and 904 b. As described elsewhere herein, the electrodeelectroactive surfaces exposed through windows 904 a and 904 b arecoated with a membrane system. An active enzyme (e.g., GOx is used ifglucose is the analyte) is disposed within or beneath or within themembrane covering one of the windows (e.g., 904 a or 904 b). Themembrane covering the other window can include inactivated enzyme (e.g.,GOx inactivated by heat, solvent, UV or laser irradiation, etc., asdescribed herein) or no enzyme. The electrode having active enzymedetects a signal related to the analyte concentration and non-analyterelated signal (e.g., due to background, etc.). In contrast, theelectrode having inactive enzyme or no enzyme detects substantially onlythe non-analyte related signal. These signals are transmitted to sensorelectronics (discussed elsewhere herein) to calculate an analyteconcentration based on only the signal component related to only theanalyte (described elsewhere herein).

In general, the windows 904 a and 904 b are separated or staggered by adistance D, which is selected to be sufficiently large thatelectroactive species (e.g., H₂O₂) do not substantially diffuse from onewindow to the other (e.g., from 904 a to 904 b). In an exemplaryembodiment of a glucose-oxidase-based sensor, active enzyme is includedin the membrane covering window 904 a and inactive enzyme is included inthe membrane covering window 904 b. Distance D is configured to be largeenough that H₂O₂ cannot diffuse from window 904 a to window 904 b, whichlacks active enzyme (as discussed elsewhere herein). In someembodiments, the distance D is at least about 0.020 inches or less toabout 0.120 inches or more. In some embodiments, D is at least about0.030 to about 0.050 inches. In other embodiments, D is at least about0.090 to about 0.095 inches. One skilled in the art appreciatesalternative embodiments of the diffusion barrier D. Namely, thediffusion barrier D can be spatial (discussed herein with relation toFIGS. 9A and 9B), physical or temporal (see discussion of DiffusionBarriers herein and FIG. 10 ). In some embodiments, a physical diffusionbarrier D, such as but not limited to an extended non-conductivestructure placed between the working electrodes (e.g., FIG. 8A),substantially prevents diffusion of H₂O₂ from one working electrode(having active enzyme) to another working electrode (having no activeenzyme). In other embodiments, a temporal diffusion barrier D is createdby pulsing or oscillating the electrical potential, such that only oneworking electrode is activated at a time.

In various embodiments, one of the windows 904 a or 904 b comprises anenzyme system configured to detect the analyte of interest (e.g.,glucose or oxygen). The other window comprises no active enzyme system(e.g., wherein the enzyme system lacks enzyme or wherein the enzyme hasbeen de-activated). In some embodiments, wherein the “enzyme systemlacks enzyme,” a layer may be applied, similar to an active enzymelayer, but without the actual enzyme included therein. In someembodiments, wherein “the enzyme has been de-activated” the enzyme canbe inactivated (e.g., by heat or solvent) prior to addition to theenzyme system solution or the enzyme can be inactivated afterapplication to the window.

In one exemplary embodiment, an enzyme is applied to both windows 904 aand 904 b followed by deactivation of the enzyme in one window. Forexample, one window can be masked (e.g., to protect the enzyme under themask) and the sensor then irradiated (to deactivate the enzyme in theunmasked window). Alternatively, one of the enzyme-coated windows (e.g.,the first window but not the second window) can be sprayed or dipped inan enzyme-deactivating solvent (e.g., treated with a protic acidsolution such a hydrochloric acid or sulfuric acid). For example, awindow coated with GOx can be dipped in dimethyl acetamide (DMAC),ethanol, or tetrahydrofuran (THF) to deactivate the GOx. In anotherexample, the enzyme-coated window can be dipped into a hot liquid (e.g.,water or saline) to deactivate the enzyme with heat.

In these embodiments, the design of the active and inactive enzymewindow is at least partially dependent upon the sensor's intended use.In some embodiments, it is preferred to deactivate the enzyme coated onwindow 904 a. In other embodiments, it is preferred to deactivate theenzyme coated on window 904 b. For example, in the case of a sensor tobe used in a host's blood stream, the choice depends upon whether thesensor will be inserted pointing upstream (e.g., against the blood flow)or pointing downstream (e.g., with the blood flow).

In one exemplary embodiment, an intravascular sensor is inserted intothe host's vein pointing upstream (against the blood flow), an enzymecoating on electrode E1 (window 904 a) is inactivated (e.g., by dippingin THF and rinsing) and an enzyme coating on electrode E2 (in window 904b) is not inactivated (e.g., by not dipping in THF). Because the enzymeon the first electrode E1 (e.g., in window 904 a) is inactive,electroactive species (e.g., H₂O₂) will not be substantially generatedat window 904 a (e.g., the first electrode E1 generates substantially noH₂O₂ to effect the second electrode E2). In contrast, the active enzymeon the second electrode E2 (in window 904 b) generates H₂O₂ which atleast partially diffuses down stream (away from the windows) and thushas no effect on the first electrode E1, other features and advantagesof spatial diffusion barriers are described in more detail elsewhereherein.

In another exemplary embodiment, an intravascular sensor is insertedinto the host's vein pointing downstream (with the blood flow), theenzyme coating on electrode E1 (window 904 a) is active and the enzymecoating on electrode E2 (in window 904 b) is inactive. Because window904 a is located farther downstream than window 904 b, the H₂O₂ producedby the enzyme in 904 a diffuses downstream (away from window 904 b), andtherefore does not affect substantially electrode E2. In a preferredembodiment, the enzyme is GOx, and the sensor is configured to detectglucose. Accordingly, H₂O₂ produced by the GOx in window 904 a does notaffect electrode E2, because the sensor is pointing downstream and theblood flow carries away the H₂O₂ produced on electrode E1.

FIGS. 9A and 9B illustrate two embodiments of a sensor having a steppedsecond end (e.g., the back end, distal end or ex vivo end, describedwith reference to FIG. 8B) that connects the sensor to the sensorelectronics. Namely, each electrode terminates within an electricalconnector 804 such as but not limited to an elastomeric electricalconnector. Additionally, each electrode is of a different length, suchthat each electrode terminates within one of a plurality of sequentialelectrical connectors. For example, with reference to FIG. 9A, thereference electrode R is the shortest in length and terminates withinthe first electrical connector 804. The first working electrode E1 islonger than the reference electrode R, and terminates within the secondelectrical connector 804. Finally, the second working electrode E2 isthe longest electrode and terminates within the third electricalconnector 804. One skilled in the art appreciates that otherconfigurations are possible. For example, the first working electrode E1can be longer than the second working electrode E2. Accordingly, thesecond working electrode E2 would terminate within the second (e.g.,middle) electrical connector 804 and the first working electrode E1would terminate within the third (e.g., last) electrical connector 804.With reference to FIG. 9B, additional stepped second end configurationsare possible. In alternative embodiments, the second ends of the sensormay be separated from each other to connect to non-parallel,non-sequential electrical connectors.

FIG. 11 is a schematic view of a sensor in yet another embodiment. Inpreferred embodiments, the sensor is integrally formed, coaxial, and hasa stepped ex vivo end (e.g., back or second end). Electrodes E1, E2 andE3 are twisted to form a helix, such as a triple helix. Additionally, atthe back end of the sensor, the electrodes are stepped and eachelectrode is individually connected to the sensor electronics by anelectrical connector 804. At each electrode's second end, the electrodeengages an electrical connector 804 that joins the electrode to thesensor electronics. For example, the second end of electrode E1electrically connects electrical connector 1106. Similarly, the secondend of electrode E2 electrically connects electrical connector 1108 andthe second end of electrode E3 electrically connects electricalconnector 1110. As described elsewhere herein, each sensor component isdifunctional, and provides electrical conductance, structural support, adiffusion barrier, or insulation (see description elsewhere herein).Although this exemplary embodiment illustrates an integrally formed,coaxial sensor having a stepped back end, one skilled in the artappreciates a variety of alternative configurations. For example, one ofthe electrodes E1, E2 or E3 can be a reference electrode, or thereference electrode can be disposed remotely from the sensor, such asbut not limited to on the host's skin. In another example, the sensorcan have only two electrodes or more than three electrodes.

One skilled in the art recognizes a variety of alternativeconfigurations for the embodiments described herein. For example, in anyembodiment of an analyte sensor, the reference electrode (and optionallya counter electrode) can be disposed remotely from the workingelectrodes. For example, in FIGS. 7A1 through 9B and FIG. 11 , thereference electrode R can be replaced with a non-conductive material,such as an insulator I. Depending upon the sensor's configuration andlocation of use, the reference electrode R can then be inserted into thehost in a location near to the sensor, applied to the host's skin, bedisposed within a fluid connector, be disposed on the ex-vivo portion ofthe sensor or even disposed on the exterior of the sensor electronics.

FIG. 7L illustrates an embodiment in which the reference and/or counterelectrode is located remotely from the first and second workingelectrodes E1 and E2, respectively. In one exemplary embodiment, thesensor is a needle-type sensor such as described with reference to FIG.1B, and the working electrodes E1, E2 are integrally formed togetherwith a substantially X-shaped insulator I and the reference electrode(and/or counter electrode) is placed on the host's skin (e.g., a button,plate, foil or wire, such as under the housing) or implantedtranscutaneously in a location separate from the working electrodes.

As another example, in one embodiment of a sensor configured to measurea host's blood, such as described in co-pending U.S. patent applicationSer. No. 11/543,396, entitled “ANALYTE SENSOR” and filed on even dateherewith, and which is incorporated herein by reference in its entirety;one or more working electrodes can be inserted into the host's blood viaa catheter and the reference and/or counter electrode can be placedwithin the a fluid connector (on the sensor) configured to be in fluidcommunication with the catheter; in such an example, the referenceand/or counter electrode is in contact with fluid flowing through thefluid connector but not in direct contact with the host's blood. Instill other embodiments, the reference and/or counter electrodes can beplaced exterior to the sensor, in bodily contact for example.

With reference to the analyte sensor embodiments disclosed herein, thesurface area of the electroactive portion of the reference (and/orcounter) electrode is at least six times the surface area of one or moreworking electrodes. In other embodiments, the reference (and/or counter)electrode surface is 1, 2, 3, 4, 5, 7, 8, 9 or 10 times the surface areaof the working electrodes. In other embodiments, the reference (and/orcounter) electrode surface area is 11, 12, 13, 14, 15, 16, 17, 18, 19 or20 times the surface area of the working electrodes. For example, in aneedle-type glucose sensor, similar to the embodiment shown in FIG. 1B,the surface area of the reference electrode (e.g., 18 or 20) includesthe exposed surface of the reference electrode, such as but not limitedto the electrode surface facing away from the working electrode 16.

In various embodiments, the electrodes can be stacked or grouped similarto that of a leaf spring configuration, wherein layers of electrode andinsulator (or individual insulated electrodes) are stacked in offsetlayers. The offset layers can be held together with bindings ofnon-conductive material, foil, or wire. As is appreciated by one skilledin the art, the strength, flexibility, and/or other material property ofthe leaf spring-configured or stacked sensor can be either modified(e.g., increased or decreased), by varying the amount of offset, theamount of binding, thickness of the layers, and/or materials selectedand their thicknesses, for example.

In some embodiments, the sensor (e.g., a glucose sensor) is configuredfor implantation into the host. For example, the sensor may be whollyimplanted into the host, such as but not limited to in the host'ssubcutaneous tissue (e.g., the embodiment shown in FIG. 1A). In otherembodiments, the sensor is configured for transcutaneous implantation inthe host's tissue. For example, the sensor can have a portion that isinserted through the host's skin and into the underlying tissue, andanother portion that remains outside the host's body (e.g., such asdescribed in more detail with reference to FIG. 1B). In still otherembodiments, the sensor is configured for indwelling in the host's bloodstream. For example, a needle-type sensor can be configured forinsertion into a catheter dwelling in a host's vein or artery. Inanother example, the sensor can be integrally formed on the exteriorsurface of the catheter, which is configured to dwell within a host'svein or artery. Examples of indwelling sensors can be found inco-pending U.S. patent application Ser. No. 11/543,396 filed on evendate herewith and entitled “ANALYTE SENSOR.” In various embodiments, thein vivo portion of the sensor can take alternative configurations, suchas but not limited to those described in more detail with reference toFIGS. 7A-9B and 11 .

In preferred embodiments, the analyte sensor substantially continuouslymeasures the host's analyte concentration. In some embodiments, forexample, the sensor can measure the analyte concentration every fractionof a second, about every fraction of a minute or every minute. In otherexemplary embodiments, the sensor measures the analyte concentrationabout every 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes. In still otherembodiments, the sensor measures the analyte concentration everyfraction of an hour, such as but not limited to every 15, 30 or 45minutes. Yet in other embodiments, the sensor measures the analyteconcentration about every hour or longer. In some exemplary embodiments,the sensor measures the analyte concentration intermittently orperiodically. In one preferred embodiment, the analyte sensor is aglucose sensor and measures the host's glucose concentration about every4-6 minutes. In a further embodiment, the sensor measures the host'sglucose concentration every 5 minutes.

In one exemplary embodiment, the analyte sensor is a glucose sensorhaving a first working electrode configured to generate a first signalassociated with both glucose and non-glucose related electroactivecompounds that have a first oxidation potential. Non-glucose relatedelectroactive compounds can be any compound, in the sensor's localenvironment that has an oxidation potential substantially overlappingwith the oxidation potential of H₂O₂, for example. While not wishing tobe bound by theory, it is believed that the glucose-measuring electrodecan measure both the signal directly related to the reaction of glucosewith GOx (produces H₂O₂ that is oxidized at the working electrode) andsignals from unknown compounds that are in the extracellular milieusurrounding the sensor. These unknown compounds can be constant ornon-constant (e.g., intermittent or transient) in concentration and/oreffect. In some circumstances, it is believed that some of these unknowncompounds are related to the host's disease state. For example, it isknow that blood chemistry changes dramatically during/after a heartattack (e.g., pH changes, changes in the concentration of various bloodcomponents/protein, and the like). Other compounds that can contributeto the non-glucose related signal are believed to be related to thewound healing process that is initiated by implantation/insertion of thesensor into the host, which is described in more detail with referenceto co-pending U.S. patent application Ser. No. 11/503,367 filed Aug. 10,2006 and entitled “ANALYTE SENSOR,” which is incorporated herein byreference in its entirety. For example, transcutaneously inserting aneedle-type sensor initiates a cascade of events that includes therelease of various reactive molecules by macrophages.

In some embodiments, the glucose sensor includes a second (e.g.,auxiliary) working electrode that is configured to generate a secondsignal associated with non-glucose related electroactive compounds thathave the same oxidation potential as the above-described first workingelectrode (e.g., para supra). In some embodiments, the non-glucoserelated electroactive species includes at least one of interferingspecies, non-reaction-related H₂O₂, and other electroactive species. Forexample, interfering species includes any compound that is not directlyrelated to the electrochemical signal generated by the glucose-GOxreaction, such as but not limited to electroactive species in the localenvironment produces by other bodily processes (e.g., cellularmetabolism, wound healing, a disease process, and the like).Non-reaction-related H₂O₂ includes H₂O₂ from sources other than theglucose-GOx reaction, such as but not limited to H₂O₂ released by nearbycells during the course of the cells' metabolism, H₂O₂ produced by otherenzymatic reactions (e.g., extracellular enzymes around the sensor orsuch as can be released during the death of nearby cells or such as canbe released by activated macrophages), and the like. Other electroactivespecies includes any compound that has an oxidation potential similar toor overlapping that of H₂O₂.

The non-analyte (e.g., non-glucose) signal produced by compounds otherthan the analyte (e.g., glucose) obscured the signal related to theanalyte, contributes to sensor inaccuracy, and is considered backgroundnoise. As described in greater detail in the section entitled “NoiseReduction,” background noise includes both constant and non-constantcomponents and must be removed to accurately calculate the analyteconcentration. While not wishing to be bound by theory, it is believedthat the sensor of the preferred embodiments are designed (e.g., withsymmetry, coaxial design and/or integral formation) such that the firstand second electrodes are influenced by substantially the sameexternal/environmental factors, which enables substantially equivalentmeasurement of both the constant and non-constant species/noise. Thisadvantageously allows the substantial elimination of noise (includingtransient biologically related noise that has been previously seen toaffect accuracy of sensor signal due to it's transient and unpredictablebehavior) on the sensor signal (using electronics described elsewhereherein) to substantially reduce or eliminate signal effects due tonoise, including non-constant noise (e.g., unpredictable biological,biochemical species or the like) known to effect the accuracy ofconventional continuous sensor signals. Preferably, the sensor includeselectronics operably connected to the first and second workingelectrodes. The electronics are configured to provide the first andsecond signals that are used to generate glucose concentration datasubstantially without signal contribution due to non-glucose-relatednoise. Preferably, the electronics include at least a potentiostat thatprovides a bias to the electrodes. In some embodiments, sensorelectronics are configured to measure the current (or voltage) toprovide the first and second signals. The first and second signals areused to determine the glucose concentration substantially without signalcontribution due to non-glucose-related noise such as by but not limitedto subtraction of the second signal from the first signal or alternativedata analysis techniques. In some embodiments, the sensor electronicsinclude a transmitter that transmits the first and second signals to areceiver, where additional data analysis and/or calibration of glucoseconcentration can be processed. U.S. Publication Nos.US-2005-0027463-A1, US-2005-0203360-A1 and US-2006-0036142-A1 describesystems and methods for processing sensor analyte data and areincorporated herein by reference in their entirety.

In preferred embodiments, the sensor electronics (e.g., electroniccomponents) are operably connected to the first and second workingelectrodes. The electronics are configured to calculate at least oneanalyte sensor data point. For example, the electronics can include apotentiostat, A/D converter, RAM, ROM, transmitter, and the like. Insome embodiments, the potentiostat converts the raw data (e.g., rawcounts) collected from the sensor to a value familiar to the host and/ormedical personnel. For example, the raw counts from a glucose sensor canbe converted to milligrams of glucose per deciliter of glucose (e.g.,mg/dl). In some embodiments, the electronics are operably connected tothe first and second working electrodes and are configured to processthe first and second signals to generate a glucose concentrationsubstantially without signal contribution due to non-glucose noiseartifacts. The sensor electronics determine the signals from glucose andnon-glucose related signal with an overlapping measuring potential(e.g., from a first working electrode) and then non-glucose relatedsignal with an overlapping measuring potential (e.g., from a secondelectrode). The sensor electronics then use these data to determine asubstantially glucose-only concentration, such as but not limited tosubtracting the second electrode's signal from the first electrode'ssignal, to give a signal (e.g., data) representative of substantiallyglucose-only concentration, for example. In general, the sensorelectronics may perform additional operations, such as but not limitedto data smoothing and noise analysis.

Bifunctionality

In some embodiments, the components of at least a portion (e.g., the invivo portion or the sensing portion) of the sensor possess bifunctionalproperties (e.g., provide at least two functions to the sensor). Theseproperties can include electrical conductance, insulative properties,structural support, and diffusion barrier properties.

In one exemplary embodiment, the analyte sensor is designed with twoworking electrodes, a membrane system and an insulating materialdisposed between the working electrodes. An active enzymatic membrane isdisposed above the first working electrode, while an inactive- ornon-enzymatic membrane is disposed above the second working electrode.Additionally, the working electrodes and the insulating material areconfigured provide at least two functions to the sensor, including butnot limited to electrical conductance, insulative properties, structuralsupport, and diffusion barrier. For example, in one embodiment of aglucose sensor, the two working electrodes support the sensor'sstructure and provide electrical conductance; the insulating materialprovides insulation between the two electrodes and provides additionalstructural support and/or a diffusional barrier.

In some embodiments, a component of the sensor is configured to provideboth electrical conductance and structural support. In an exemplaryembodiment, the working electrode(s) and reference electrode aregenerally manufactured of electrically conductive materials, such as butnot limited silver or silver/silver chloride, copper, gold, platinum,iridium, platinum-iridium, palladium, graphite, carbon, conductivepolymers, alloys, and the like. Accordingly, the electrodes are bothconductive and they give the sensor its shape (e.g., are supportive).

Referring to FIG. 1B, all three electrodes 16, 18, and 20 aremanufactured from plated insulator, a plated wire, or electricallyconductive material, such as but not limited to a metal wire.Accordingly, the three electrodes provide both electrical conductance(to measure glucose concentration) and structural support. Due to theconfiguration of the electrodes (e.g., the wires are about 0.001 inchesin diameter or less, to about 0.01 inches or more), the sensor isneedle-like and only about 0.003 inches or less to about 0.015 inches ormore.

Similarly, the electrodes of FIG. 7A through FIG. 9 provide electricalconductance, to detect the analyte of interest, as well as structuralsupport for the sensor. For example, the sensors depicted in FIGS. 7Athrough 7L embodiments that are substantially needle-like. Additionally,these sensors are substantially resilient, and therefore able to flex inresponse to mechanical pressure and then to regain their originalshapes. FIG. 7M depicts a cross-section of another sensor embodiment,which can be a composite (e.g., built up of layers of working andreference electrode materials) needle-like sensor or the composite“wire” can be cut to produce pancake-shaped sensors [describe itsbifunctionality without unnecessary characterizations (e.g., not“pancake-shaped”). FIG. 7N through FIG. 9 illustrate additional sensorembodiments, wherein the electrodes provide electrical conductance andsupport the sensor's needle-like shape.

In some embodiments, the first and second working electrodes areconfigured to provide both electrical conductance and structuralsupport. For example, in a needle-type sensor, the working electrodesare often manufactured of bulk metal wires (e.g., copper, gold,platinum, iridium, platinum-iridium, palladium, graphite, carbon,conductive polymers, alloys, and the like). The reference electrode,which can function as a reference electrode alone, or as a dualreference and counter electrode, are formed from silver or silver/silverchloride, or the like. The metal wires are conductive (e.g., can conductelectricity) and give the sensor its shape and/or structural support.For example, one electrode metal wire may be coiled around the otherelectrode metal wire (e.g., FIG. 1B or FIG. 7B). In a furtherembodiment, the sensor includes a reference electrode that is alsoconfigured to provide electrical conductance and structural support(e.g., FIG. 1B, FIGS. 7C to 7E). In general, reference electrodes aremade of metal, such as bulk silver or silver/silver chloride wires. Likethe two working electrodes, the reference electrode both conductselectricity and supports the structure of the sensor.

In some embodiments, the first and second working electrode and theinsulating material are configured provide at least two functions, suchas but not limited to electrical conductance, insulative properties,structural support, and diffusion barrier. As described elsewhereherein, the working electrodes are electrical conductors and alsoprovide support for the sensor. The insulating material (e.g., I) actsas an insulator, to prevent electrical communication between certainparts of the various electrodes. The insulating material also providesstructural support or substantially prevents diffusion of electroactivespecies from one working electrode to the other, which is discussed ingreater detail elsewhere herein.

In preferred embodiments, the sensor has a diffusion barrier disposedbetween the first and second working electrodes. The diffusion barrieris configured to substantially block diffusion of the analyte or aco-analyte (e.g., H₂O₂) between the first and second working electrodes.For example, a sheet of a polymer through which H₂O₂ cannot diffuse canbe interposed between the two working electrodes. Diffusion barriers arediscussed in greater detail elsewhere herein.

In some embodiments of the preferred embodiments, the analyte sensorincludes a reference electrode that is configured to provide electricalconductance and a diffusion barrier. Electrical conductance is aninherent property of the metal used to manufacture the referenceelectrode. However, the reference electrode can be configured to preventspecies (e.g., H₂O₂) from diffusing from the first working electrode tothe second working electrode. For example, a sufficiently largereference electrode can be placed between the two working electrodes. Insome embodiments, the reference electrode projects farther than the twoworking electrodes. In other embodiments, the reference electrode is sobroad that a substantial portion of the H₂O₂ produced at the firstworking electrode cannot diffuse to the second working electrode, andthereby significantly affect the second working electrode's function.

In a further embodiment, the reference electrode is configured toprovide a diffusion barrier and structural support. As describedelsewhere herein, the reference electrode can be constructed of asufficient size and/or shape that a substantial portion of the H₂O₂produced at a first working electrode cannot diffuse to the secondworking electrode and affect the second working electrode's function.Additionally, metal wires are generally resilient and hold their shape,the reference electrode can also provide structural support to thesensor (e.g., help the sensor to hold its shape).

In some embodiments of the analyte sensor described elsewhere herein,the insulating material is configured to provide both electricalinsulative properties and structural support. In one exemplaryembodiment, portions of the electrodes are coated with a non-conductivepolymer. Inherently, the non-conductive polymer electrically insulatesthe coated electrodes from each other, and thus substantially preventspassage of electricity from one coated wire to another coated wire.Additionally, the non-conductive material (e.g., a non-conductivepolymer or insulating material) can stiffen the electrodes and make themresistant to changes in shape (e.g., structural changes).

In some embodiments, a sensor component is configured to provideelectrical insulative properties and a diffusion barrier. In oneexemplary embodiment, the electrodes are coated with the non-conductivematerial that substantially prevents direct contact between theelectrodes, such that electricity cannot be conducted directly from oneelectrode to another. Due to the non-conductive coatings on theelectrodes, electrical current must travel from one electrode to anotherthrough the surrounding aqueous medium (e.g., extracellular fluid,blood, wound fluid, or the like). Any non-conductive material (e.g.,insulator) known in the art can be used to insulate the electrodes fromeach other. In exemplary embodiments, the electrodes can be coated withnon-conductive polymer materials (e.g., parylene, PTFE, ETFE,polyurethane, polyethylene, polyimide, silicone and the like) bydipping, painting, spraying, spin coating, or the Non-conductivematerial (e.g., insulator, as discussed elsewhere herein) applied to orseparating the electrodes can be configured to prevent diffusion ofelectroactive species (e.g., H₂O₂) from one working electrode to anotherworking electrode. Diffusion of electroactive species from one workingelectrode to another can cause a false analyte signal. For example,electroactive species (e.g., H₂O₂) that are created at a first workingelectrode having active enzyme (e.g., GOx) can diffuse to a nearbyworking electrode (e.g., without active GOx). When the electroactivespecies arrives at the second working electrode, the second electroderegisters a signal (e.g., as if the second working electrode comprisedactive GOx). The signal registered at the second working electrode dueto the diffusion of the H₂O₂ is aberrant and can cause improper dataprocessing in the sensor electronics. For example, if the secondelectrode is configured to measure a substantially non-analyte relatedsignal (e.g., background) the sensor will record a higher non-analyterelated signal than is appropriate, possibly resulting in the sensorreporting a lower analyte concentration than actually is present in thehost. This is discussed in greater detail elsewhere herein.

In preferred embodiments, the non-conductive material is configured toprovide a diffusion barrier and structural support to the sensor.Diffusion barriers are described elsewhere herein. Non-conductivematerials can be configured to support the sensor's structure. In some,non-conductive materials with relatively more or less rigidity can beselected. For example, if the electrodes themselves are relativelyflexible, it may be preferred to select a relatively rigidnon-conductive material, to make the sensor stiffer (e.g., less flexibleor bendable). In another example, if the electrodes are sufficientlyresilient or rigid, a very flexible non-conductive material may becoated on the electrodes to bind the electrodes together (e.g., keep theelectrodes together and thereby hold the sensor's shape).

Referring now to FIGS. 7C to 7J, the non-conductive material can becoated on or wrapped around the grouped or bundled electrodes, toprevent the electrodes from separating and also to prevent theelectrodes from directly touching each other. For example, withreference to FIG. 7C, each electrode can be individually coated by afirst non-conductive material and then bundled together. Then the bundleof individually insulated electrodes can be coated with a second layerof the first non-conductive material or with a layer or a secondnon-conductive material. In an embodiment of a sensor having thestructure shown in FIG. 7K, each electrode E1, E2 is coated with anon-conductive material/insulator I, and then coated with a secondnon-conductive material 703 (e.g., instead of a biointerface membrane).Similarly, in FIG. 7L, the non-conductive material I prevents electrodesE1 and E2 from making direct contact with each other as well as givingthe needle-like sensor its overall dimensions and shape.

FIG. 7N illustrates one method of configuring a sensor having anon-conductive material I that both provides electrical insulationbetween the electrodes E1, E2, R and provides structural support to thesensor. Namely, the electrodes are embedded in a non-conductive polymerI, which is subsequently vulcanized (704=before shaping). Aftervulcanization, the excess non-conductive polymer I is trimmed away(e.g., cutting or scraping, etc.) to produce a sensor having the finaldesired sensor shape 705=after shaping).

In some embodiments, a component of the sensor is configured to provideboth insulative properties and a diffusion barrier. Diffusion barriersare discussed elsewhere herein. In one exemplary embodiment, the workingelectrodes are separated by a non-conductive material/insulator that isconfigured such that electroactive species (e.g., H₂O₂) cannot diffusearound it (e.g., from a first electrode to a second electrode). Forexample, with reference to the embodiment shown in FIG. 7H, theelectrodes E1, E2 are placed in the groves carved into a cylinder ofnon-conductive material I. The distance D from E1 to E2 (e.g., around I)is sufficiently great that H₂O₂ produced at E1 cannot diffuse to E2 andthereby cause an aberrant signal at E2.

In some preferred embodiments, in addition to two working electrodes anda non-conductive material/insulator, the sensor includes at least areference or a counter electrode. In preferred embodiments, thereference and/or counter electrode, together with the first and secondworking electrodes, integrally form at least a portion of the sensor. Insome embodiments, the reference and/or counter electrode is locatedremote from the first and second working electrodes. For example, insome embodiments, such as in the case of a transcutaneous sensor, thereference and/or counter electrodes can be located on the ex vivoportion of the sensor or reside on the host's skin, such as a portion ofan adhesive patch. In other embodiments, such as in the case of anintravascular sensor, the reference and/or counter electrode can belocated on the host's skin, within or on the fluid connector (e.g.,coiled within the ex vivo portion of the device and in contact withfluid within the device, such as but not limited to saline) or on theexterior of the ex vivo portion of the device. In preferred embodiments,the surface area of the reference and/or counter electrode is as leastsix times the surface area of at least one of the first and secondworking electrodes. In a further embodiment, the surface area of thereference and/or counter electrode is at least ten times the surfacearea of at least one of the first and second electrodes.

In preferred embodiments, the sensor is configured for implantation intothe host. The sensor can be configured for subcutaneous implantation inthe host's tissue (e.g., transcutaneous or wholly implantable).Alternatively, the sensor can be configured for indwelling in the host'sblood stream (e.g., inserted through an intravascular catheter orintegrally formed on the exterior surface of an intravascular catheterthat is inserted into the host's blood stream).

In some embodiments, the sensor is a glucose sensor that has a firstworking electrode configured to generate a first signal associated withglucose (e.g., the analyte) and non-glucose related electroactivecompounds (e.g., physiological baseline, interferents, and non-constantnoise) having a first oxidation potential. For example, glucose has afirst oxidation potential. The interferents have an oxidation potentialthat is substantially the same as the glucose oxidation potential (e.g.,the first oxidation potential). In a further embodiment, the glucosesensor has a second working electrode that is configured to generate asecond signal associated with noise of the glucose sensor. The noise ofthe glucose sensor is signal contribution due to non-glucose relatedelectroactive compounds (e.g., interferents) that have an oxidationpotential that substantially overlaps with the first oxidation potential(e.g., the oxidation potential of glucose, the analyte). In variousembodiments, the non-glucose related electroactive species include aninterfering species, non-reaction-related hydrogen peroxide, and/orother electroactive species.

In preferred embodiments, the glucose sensor has electronics that areoperably connected to the first and second working electrodes and areconfigured to provide the first and second signals to generate glucoseconcentration data substantially without signal contribution due tonon-glucose-related noise. For example, the sensor electronics analyzethe signals from the first and second working electrodes and calculatethe portion of the first electrode signal that is due to glucoseconcentration only. The portion of the first electrode signal that isnot due to the glucose concentration can be considered to be background,such as but not limited to noise.

In preferred embodiments, the glucose sensor has a non-conductivematerial (e.g., insulative material) positioned between the first andsecond working electrodes. The non-conductive material substantiallyprevents cross talk between the first and second working electrodes. Forexample, the electrical signal cannot pass directly from a firstinsulated electrode to a second insulated electrode. Accordingly, thesecond insulated electrode cannot aberrantly record an electrical signaldue to electrical signal transfer from the first insulated electrode.

In preferred embodiments, the first and second working electrodes andthe non-conductive material integrally form at least a portion of thesensor (e.g., a glucose sensor). The first and second working electrodesintegrally form a substantial portion of the sensor configured forinsertion in the host (e.g., the in vivo portion of the sensor). In afurther embodiment, the sensor (e.g., a glucose sensor) includes areference electrode that, in addition to the first and second workingelectrodes, integrally forms a substantial portion of the sensorconfigured for insertion in the host (e.g., the in vivo portion of thesensor). In yet a further embodiment, the sensor (e.g., a glucosesensor) has an insulator (e.g., non-conductive material), wherein thefirst and second working electrodes and the insulator integrally form asubstantial portion of the sensor configured for insertion in the host(e.g., the in vivo portion of the sensor).

In preferred embodiments, the sensor (e.g., a glucose sensor) includes adiffusion barrier configured to substantially block diffusion of theanalyte (e.g., glucose) or a co-analyte (e.g., H₂O₂) between the firstand second working electrodes. For example, as described with referenceto FIG. 10 , a diffusion barrier D (e.g., spatial, physical and/ortemporal) blocks diffusion of a species (e.g., glucose and/or H₂O₂) fromthe first working electrode E1 to the second working electrode E2. Insome embodiments, the diffusion barrier D is a physical diffusionbarrier, such as a structure between the working electrodes that blocksglucose and H₂O₂ from diffusing from the first working electrode E1 tothe second working electrode E2. In other embodiments, the diffusionbarrier D is a spatial diffusion barrier, such as a distance between theworking electrodes that blocks glucose and H₂O₂ from diffusing from thefirst working electrode E1 to the second working electrode E2. In stillother embodiments, the diffusion barrier D is a temporal diffusionbarrier, such as a period of time between the activity of the workingelectrodes such that if glucose or H₂O₂ diffuses from the first workingelectrode E1 to the second working electrode E2, the second workingelectrode E2 will not substantially be influenced by the H₂O₂ from thefirst working electrode E1.

With reference to FIG. 7H, if the diffusion barrier is spatial, adistance D separates the working electrodes, such that the analyte orco-analyte substantially cannot diffuse from a first electrode E1 to asecond electrode E2. In some embodiments, the diffusion barrier isphysical and configured from a material that substantially preventsdiffusion of the analyte or co-analyte there through. Again referring toFIG. 7H, the insulator I and/or reference electrode R is configured froma material that the analyte or co-analyte cannot substantially passthrough. For example, H₂O₂ cannot substantially pass through asilver/silver chloride reference electrode. In another example, aparylene insulator can prevent H₂O₂ diffusion between electrodes. Insome embodiments, wherein the diffusion barrier is temporal, the twoelectrodes are activated at separate, non-overlapping times (e.g.,pulsed). For example, the first electrode E1 can be activated for aperiod of one second, followed by activating the second electrode E2three seconds later (e.g., after E1 has been inactivated) for a periodof one second.

In additional embodiments, a component of the sensor is configured toprovide both a diffusional barrier and a structural support, asdiscussed elsewhere herein. Namely, the diffusion barrier can beconfigured of a material that is sufficiently rigid to support thesensor's shape. In some embodiments, the diffusion barrier is anelectrode, such as but not limited to the reference and counterelectrodes (e.g., FIG. 7G to 7J and FIG. 8A). In other embodiments, thediffusion barrier is an insulating coating (e.g., parylene) on anelectrode (e.g., FIG. 7K to 7L) or an insulating structure separatingthe electrodes (e.g., FIG. 8A and FIG. 10 ).

One preferred embodiment provides a glucose sensor configured forinsertion into a host for measuring a glucose concentration in the host.The sensor includes a first working electrode configured to generate afirst signal associated with glucose and non-glucose relatedelectroactive compounds having a first oxidation potential. The sensoralso includes a second working electrode configured to generate a secondsignal associated with noise of the glucose sensor comprising signalcontribution due to non-glucose related electroactive compounds thathave an oxidation potential that substantially overlaps with the firstoxidation potential (e.g., the oxidation potential of H₂O₂).Additionally, the glucose sensor includes a non-conductive materiallocated between the first and second working electrodes. Each of thefirst working electrode, the second working electrode, and thenon-conductive material are configured to provide at least two functionsselected from the group consisting of: electrical conductance,insulative properties, structural support, and diffusion barrier.

In some embodiments of the glucose sensor, each of the first workingelectrode and the second working electrode are configured to provideelectrical conductance and structural support. For example, the metalplated wire of electrodes conducts electricity and helps maintain thesensor's shape. In a further embodiment, the glucose sensor includes areference electrode that is configured to provide electrical conductanceand structural support. For example, the silver/silver chloridereference electrode is both electrically conductive and supports thesensor's shape. In some embodiments of the glucose sensor includes areference electrode that is configured to provide electrical conductanceand a diffusion barrier. For example, the silver/silver chloridereference electrode can be configured as a large structure or protrudingstructure, which separates the working electrodes by the distance D(e.g., FIG. 7G). Distance “D” is sufficiently large that glucose and/orH₂O₂ cannot substantially diffuse around the reference electrode.Accordingly, H₂O₂ produced at a first working electrode does notsubstantially contribute to signal at a second working electrode. Insome embodiments of the glucose sensor includes a reference electrodethat is configured to provide a diffusion barrier and structuralsupport. In some embodiments of the glucose sensor, the non-conductivematerial is configured to provide electrical insulative properties andstructural support. For example, non-conductive dielectric materials caninsulate an electrode and can be sufficiently rigid to stiffen thesensor. In still other embodiments, the non-conductive material isconfigured to provide electrical insulative properties and a diffusionbarrier. For example, a substantially rigid, non-conductive dielectriccan coat the electrodes and provide support, as shown in FIG. 7L. Inother embodiments, the non-conductive material is configured to providediffusion barrier and structural support. For example, a dielectricmaterial can protrude between the electrodes, to act as a diffusionbarrier and provide support to the sensor's shape, as shown in FIG. 10 .

Noise Reduction

In another aspect, the sensor is configured to reduce noise, includingnon-constant non-analyte related noise with an overlapping measuringpotential with the analyte. A variety of noise can occur when a sensorhas been implanted in a host. Generally, implantable sensors measure asignal (e.g., counts) that generally comprises at least two components,the background signal (e.g., background noise) and the analyte signal.The background signal is composed substantially of signal contributiondue to factors other than glucose (e.g., interfering species,non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation potential that overlaps with the analyte orco-analyte). The analyte signal (e.g., glucose) is composedsubstantially of signal contribution due to the analyte. Consequently,because the signal includes these two components, a calibration isperformed in order to determine the analyte (e.g., glucose)concentration by solving for the equation y=mx+b, where the value of brepresents the background of the signal.

In some circumstances, the background is comprised of both constant(e.g., baseline) and non-constant (e.g., noise) factors. Generally, itis desirable to remove the background signal, to provide a more accurateanalyte concentration to the host or health care professional.

The term “baseline” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substantially constant signal derivedfrom certain electroactive compounds found in the human body that arerelatively constant (e.g., baseline of the host's physiology,non-analyte related). Therefore, baseline does not significantlyadversely affect the accuracy of the calibration of the analyteconcentration (e.g., baseline can be relatively constantly eliminatedusing the equation y=mx+b).

In contrast, “noise” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substantially intermittent signal causedby relatively non-constant factors (e.g., the presence of intermittentnoise-causing compounds that have an oxidation potential thatsubstantially overlaps the oxidation potential of the analyte orco-analyte and arise due to the host's ingestion, metabolism, woundhealing, and other mechanical, chemical and/or biochemical factors, alsonon-analyte related). Noise can be difficult to remove from the sensorsignal by calibration using standard calibration equations (e.g.,because the background of the signal does not remain constant). Noisecan significantly adversely affect the accuracy of the calibration ofthe analyte signal. Additionally noise, as described herein, can occurin the signal of conventional sensors with electrode configurations thatare not particularly designed to measure noise substantially equally atboth active and in-active electrodes (e.g., wherein the electrodes arespaced and/or non symmetrical, noise may not be equally measured andtherefore not easily removed using conventional dual electrode designs).

There are a variety of ways noise can be recognized and/or analyzed. Inpreferred embodiments, the sensor data stream is monitored, signalartifacts are detected, and data processing is based at least in part onwhether or not a signal artifact has been detected, such as described inU.S. Publication No. US-2005-0043598-A1 and co-pending U.S. applicationSer. No. 11/503,367 filed Aug. 10, 2006 and entitled “ANALYTE SENSOR,”herein incorporated by reference in its entirety.

Accordingly, if a sensor is designed such that the signal contributiondue to baseline and noise can be removed, then more accurate analyteconcentration data can be provided to the host or a healthcareprofessional.

One embodiment provides an analyte sensor (e.g., glucose sensor)configured for insertion into a host for measuring an analyte (e.g.,glucose) in the host. The sensor includes a first working electrodedisposed beneath an active enzymatic portion of a membrane on thesensor; a second working electrode disposed beneath an inactive- ornon-enzymatic portion of the membrane on the sensor; and electronicsoperably connected to the first and second working electrode andconfigured to process the first and second signals to generate ananalyte (e.g., glucose) concentration substantially without signalcontribution due to non-glucose related noise artifacts.

Referring now to FIG. 9B, in another embodiment, the sensor has a firstworking electrode E1 and a second working electrode E2. The sensorincludes a membrane system (not shown) covering the electrodes, asdescribed elsewhere herein. A portion of the membrane system on thefirst electrode contains active enzyme, which is depicted schematicallyas oval 904 a (e.g., active GOx). A portion of the membrane system onthe second electrode is non-enzymatic or contains inactivated enzyme,which is depicted schematically as oval 904 b (e.g., heat- orchemically-inactivated GOx or optionally no GOx). A portion of thesensor includes electrical connectors 804. In some embodiments, theconnectors 804 are located on an ex vivo portion of the sensor. Eachelectrode (e.g., E1, E2, etc.) is connected to sensor electronics (notshown) by a connector 804. Since the first electrode E1 includes activeGOx, it produces a first signal that is related to the concentration ofthe analyte (in this case glucose) in the host as well as other speciesthat have an oxidation potential that overlaps with the oxidationpotential of the analyte or co-analyte (e.g., non-glucose related noiseartifacts, noise-causing compounds, background). Since the secondelectrode E2 includes inactive GOx, it produces a second signal that isnot substantially related to the analyte or co-analyte. Instead, thesecond signal is substantially related to noise-causing compounds andother background noise. The sensor electronics process the first andsecond signals to generate an analyte concentration that issubstantially free of the non-analyte related noise artifacts.Elimination or reduction of noise (e.g., non-constant background) isattributed at least in part to the configuration of the electrodes inthe preferred embodiments, e.g., the locality of first and secondworking electrode, the symmetrical or opposing design of the first andsecond working electrodes, and/or the overall sizing and configurationof the exposed electroactive portions. Accordingly, the host is providedwith improved analyte concentration data, upon which he can make medicaltreatment decisions (e.g., if he should eat, if he should takemedication or the amount of medication he should take). Advantageously,in the case of glucose sensors, since the sensor can provide improvedquality of data, the host can be maintained under tighter glucosecontrol (e.g., about 80 mg/dl to about 120 mg/dl) with a reduced risk ofhypoglycemia and hypoglycemia's immediate complications (e.g., coma ordeath). Additionally, the reduced risk of hypoglycemia makes it possibleto avoid the long-term complications of hyperglycemia (e.g., kidney andheart disease, neuropathy, poor healing, loss of eye sight) byconsistently maintaining tight glucose control (e.g., about 80 mg/dl toabout 120 mg/dl).

In one embodiment, the sensor is configured to substantially eliminate(e.g., subtract out) noise due to mechanical factors. Mechanical factorsinclude macro-motion of the sensor, micro-motion of the sensor, pressureon the sensor, local tissue stress, and the like. Since both workingelectrodes are constructed substantially symmetrically and identically,and due to the sensor's small size, the working electrodes aresubstantially equally affected by mechanical factors impinging upon thesensor. For example, if a build-up of noise-causing compounds occurs(e.g., due to the host pressing upon and manipulating (e.g., fiddlingwith) the sensor, for example) both working electrodes will measure theresulting noise to substantially the same extend, while only one workingelectrode (the first working electrode, for example) will also measuresignal due to the analyte concentration in the host's body. The sensorthen calculates the analyte signal (e.g., glucose-only signal) byremoving the noise that was measured by the second working electrodefrom the total signal that was measured by the first working electrode.

Non-analyte related noise can also be caused by biochemical and/orchemical factors (e.g., compounds with electroactive acidic, amine orsulfhydryl groups, urea, lactic acid, phosphates, citrates, peroxides,amino acids (e.g., L-arginine), amino acid precursors or break-downproducts, nitric oxide (NO), NO-donors, NO-precursors or otherelectroactive species or metabolites produced during cell metabolismand/or wound healing). As with noise due to mechanical factors, noisedue to biochemical/chemical factors will impinge upon the two workingelectrodes of the preferred embodiments (e.g., with and without activeGOx) about the same extent, because of the sensor's small size andsymmetrical configuration. Accordingly, the sensor electronics can usethese data to calculate the glucose-only signal, as described elsewhereherein.

In one exemplary embodiment, the analyte sensor is a glucose sensor thatmeasures a first signal associated with both glucose and non-glucoserelated electroactive compounds having a first oxidation potential. Forexample, the oxidation potential of the non-glucose relatedelectroactive compounds substantially overlaps with the oxidationpotential of H₂O₂, which is produced according to the reaction ofglucose with GOx and subsequently transfers electrons to the firstworking electrode (e.g., E1; FIG. 10 ). The glucose sensor also measuresa second signal, which is associated with background noise of theglucose sensor. The background noise is composed of signal contributiondue to noise-causing compounds (e.g., interferents),non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation potential that substantially overlaps with theoxidation potential of H₂O₂ (the co-analyte). The first and secondworking electrodes integrally form at least a portion of the sensor,such as but not limited to the in vivo portion of the sensor, asdiscussed elsewhere herein. Additionally, each of the first workingelectrode, the second working electrode, and a non-conductivematerial/insulator are configured provide at least two functions (to thesensor), such as but not limited to electrical conductance, insulativeproperties, structural support, and diffusion barrier (describedelsewhere herein). Furthermore, the sensor has a diffusion barrier thatsubstantially blocks diffusion of glucose or H₂O₂ between the first andsecond working electrodes.

Diffusion Barrier

Another aspect of the sensor is a diffusion barrier, to prevent anundesired species, such as H₂O₂ or the analyte, from diffusing betweenactive (with active enzyme) and inactive (without active enzyme)electrodes. In various embodiments, the sensor includes a diffusionbarrier configured to be physical, spatial, and/or temporal.

FIG. 10 is a schematic illustrating one embodiment of a sensor (e.g., aportion of the in vivo portion of the sensor, such as but not limited tothe sensor electroactive surfaces) having one or more components thatact as a diffusion barrier (e.g., prevent diffusion of electroactivespecies from one electrode to another). The first working electrode E1is coated with an enzyme layer 1000 comprising active enzyme. Forexample, in a glucose sensor, the first working electrode E1 is coatedwith glucose oxidase enzyme (GOx). A second working electrode E2 isseparated from the first working electrode E1 by a diffusion barrier D,such as but not limited to a physical diffusion barrier (e.g., either areference electrode or a layer of non-conductive material/insulator).The diffusion barrier can also be spatial or temporal, as discussedelsewhere herein.

Glucose and oxygen diffuse into the enzyme layer 1000, where they reactwith GOx, to produce gluconate and H₂O₂. At least a portion of the H₂O₂diffuses to the first working electrode E1, where it iselectrochemically oxidized to oxygen and transfers two electrons (e.g.,2e⁻) to the first working electrode E1, which results in a glucosesignal that is recorded by the sensor electronics (not shown). Theremaining H₂O₂ can diffuse to other locations in the enzyme layer or outof the enzyme layer (illustrated by the wavy arrows). Without adiffusion barrier D, a portion of the H₂O₂ can diffuse to the secondworking electrode E2, which results in an aberrant signal that can berecorded by the sensor electronics as a non-glucose related signal(e.g., background).

Preferred embodiments provide for a substantial diffusion barrier Dbetween the first and second working electrodes (E1, E2) such that theH₂O₂ cannot substantially diffuse from the first working electrode E1 tothe second working electrode E2. Accordingly, the possibility of anaberrant signal produced by H₂O₂ from the first working electrode E1 (atthe second working electrode E2) is reduced or avoided.

In some alternative embodiments, the sensor is provided with a spatialdiffusion barrier between electrodes (e.g., the working electrodes). Forexample, a spatial diffusion barrier can be created by separating thefirst and second working electrodes by a distance that is too great forthe H₂O₂ to substantially diffuse between the working electrodes. Insome embodiments, the spatial diffusion barrier is about 0.010 inches toabout 0.120 inches. In other embodiments, the spatial diffusion barrieris about 0.020 inches to about 0.050 inches. Still in other embodiments,the spatial diffusion barrier is about 0.055 inches to about 0.095inches. A reference electrode R (e.g., a silver or silver/silverchloride electrode) or a non-conductive material I (e.g., a polymerstructure or coating such as Parylene) can be configured to act as aspatial diffusion barrier.

FIGS. 9A and 9B illustrate two exemplary embodiments of sensors withspatial diffusion barriers. In each embodiment, the sensor has twoworking electrodes E1 and E2. Each working electrode includes anelectroactive surface, represented schematically as windows 904 a and904 b, respectively. The sensor includes a membrane system (not shown).Over one electroactive surface (e.g., 904 a) the membrane includesactive enzyme (e.g., GOx). Over the second electroactive surface (e.g.,904 b) the membrane does not include active enzyme. In some embodiments,the portion of the membrane covering the second electroactive surfacecontains inactivated enzyme (e.g., heat- or chemically-inactivated GOx)while in other embodiments, this portion of the membrane does notcontain any enzyme (e.g., non-enzymatic). The electroactive surfaces 904a and 904 b are separated by a spatial diffusion barrier that issubstantially wide such that H₂O₂ produced at the first electroactivesurface 904 a cannot substantially affect the second electroactivesurface 904 b. In some alternative embodiments, the diffusion barriercan be physical (e.g., a structure separating the electroactivesurfaces) or temporal (e.g., oscillating activity between theelectroactive surfaces).

In another embodiment, the sensor is an indwelling sensor, such asconfigured for insertion into the host's circulatory system via a veinor an artery. In some exemplary embodiments, an indwelling sensorincludes at least two working electrodes that are inserted into thehost's blood stream through a catheter. The sensor includes at least areference electrode that can be disposed either with the workingelectrodes or remotely from the working electrodes. The sensor includesa spatial, a physical, or a temporal diffusion barrier. A spatialdiffusion barrier can be configured as described elsewhere herein, withreference to FIG. 7A through FIG. 8A.

FIG. 9B provides one exemplary embodiment of an indwelling analytesensor, such as but not limited to an intravascular glucose sensor to beused from a few hours to ten days or longer. Namely, the sensor includestwo working electrodes. One working electrode detects theglucose-related signal (due to active GOx applied to the electroactivesurface) as well as non-glucose related signal. The other workingelectrode detects only the non-glucose related signal (because no activeGOx is applied to its electroactive surface). H₂O₂ is produced on theworking electrode with active GOx. If the H₂O₂ diffuses to the otherworking electrode (the no GOx electrode) an aberrant signal will bedetected at this electrode, resulting in reduced sensor activity.Accordingly, it is desirable to separate the electroactive surfaces witha diffusion barrier, such as but not limited to a spatial diffusionbarrier. Indwelling sensors are described in more detail in copendingU.S. patent application Ser. No. 11/543,396 filed on even date herewithand entitled “ANALYTE SENSOR,” herein incorporated in its entirety byreference.

To configure a spatial diffusion barrier between the working electrodes,the location of the active enzyme (e.g., GOx) is dependent upon theorientation of the sensor after insertion into the host's artery orvein. For example, in an embodiment configured for insertion upstream inthe host's blood flow (e.g., against the blood flow), active GOx wouldbe applied to electroactive surface 904 b and inactive GOX (or no GOx)would be applied to electroactive surface 904 a (e.g., upstream from 904b, relative to the direction of blood flow). Due to this configuration,H₂O₂ produced at electroactive surface 904 b would be carrier downstream (e.g., away from electroactive surface 904 a) and thus not affectelectrode E1.

Alternatively, the indwelling electrode can also be configured forinsertion of the sensor into the host's vein or artery in the directionof the blood flow (e.g., pointing downstream). In this configuration,referred to as a spatial diffusion barrier, or as a flow path diffusionbarrier, the active GOx can be advantageously applied to electroactivesurface 904 a on the first working electrode E1. The electroactivesurface 904 b on the second working electrode E2 has no active GOx.Accordingly, H₂O₂ produced at electroactive surface 904 a is carriedaway by the blood flow, and has no substantial effect on the secondworking electrode E2.

In another embodiment of an indwelling analyte sensor, the referenceelectrode, which is generally configured of silver/silver chloride, canextend beyond the working electrodes, to provide a physical barrieraround which the H₂O₂ generated at the electrode comprising active GOxcannot pass the other working electrode (that has active GOx). In someembodiments, the reference electrode has a surface area that is at leastsix times larger than the surface area of the working electrodes. Inother embodiments, a 2-working electrode analyte sensor includes acounter electrode in addition to the reference electrode. As isgenerally know in the art, the inclusion of the counter electrode allowsfor a reduction in the reference electrode's surface area, and therebyallows for further miniaturization of the sensor (e.g., reduction in thesensor's diameter and/or length, etc.).

FIG. 7H provides one exemplary embodiment of a spatial diffusionbarrier, wherein the reference electrode/non-conductive insulatingmaterial R/I is sized and shaped such that H₂O₂ produced at the firstworking electrode E1 (e.g., with enzyme) does not substantially diffusearound the reference electrode/non-conductive material R/I to the secondworking electrode E2 (e.g., without enzyme). In another example, shownin FIG. 7J, the X-shaped the reference electrode/non-conductive materialR/I substantially prevents diffusion of electroactive species from thefirst working electrode E1 (e.g., with enzyme) to the second workingelectrode E2 (e.g., without enzyme). In another embodiment, such as thesensor shown in FIG. 7A, the layer of non-conductive material I (betweenthe electrodes) is of a sufficient length that the H₂O₂ produced at oneelectrode cannot substantially diffuse to another electrode. (e.g., fromE1 to either E2 or E3; or from E2 to either E1 or E3, etc.).

In some embodiments, a physical diffusion barrier is provided by aphysical structure, such as an electrode, insulator, and/or membrane.For example, in the embodiments shown in FIGS. 7G to 7J, the insulator(I) or reference electrode (R) act as a diffusion barrier. As anotherexample, the diffusion barrier can be a bioprotective membrane (e.g., amembrane that substantially resists or blocks the transport of a species(e.g., hydrogen peroxide), such as CHRONOTHANE®-H (apolyetherurethaneurea based on polytetramethylene glycol, polyethyleneglycol, methylene diisocyanate, and organic amines). As yet anotherexample, the diffusion barrier can be a resistance domain, as describedin more detail elsewhere herein; namely, a semipermeable membrane thatcontrols the flux of oxygen and an analyte (e.g., glucose) to theunderlying enzyme domain. Numerous other structures and membranes canfunction as a physical diffusion barrier as is appreciated by oneskilled in the art.

In other embodiments, a temporal diffusion barrier is provided (e.g.,between the working electrodes). By temporal diffusion barrier is meanta period of time that substantially prevents an electroactive species(e.g., H₂O₂) from diffusing from a first working electrode to a secondworking electrode. For example, in some embodiments, the differentialmeasurement can be obtained by switching the bias potential of eachelectrode between the measurement potential and a non-measurementpotential. The bias potentials can be held at each respective setting(e.g., high and low bias settings) for as short as milliseconds to aslong as minutes or hours. Pulsed amperometric detection (PED) is onemethod of quickly switching voltages, such as described in Bisenberger,M.; Brauchle, C.; Hampp, N. A triple-step potential waveform at enzymemultisensors with thick-film gold electrodes for detection of glucoseand sucrose. Sensors and Actuators 1995, B, 181-189, which isincorporated herein by reference in its entirety. In some embodiments,bias potential settings are held long enough to allow equilibration.

One preferred embodiment provides a glucose sensor configured forinsertion into a host for measuring glucose in the host. The sensorincludes first and second working electrodes and an insulator locatedbetween the first and second working electrodes. The first workingelectrode is disposed beneath an active enzymatic portion of a membraneon the sensor and the second working electrode is disposed beneath aninactive- or non-enzymatic portion of the membrane on the sensor. Thesensor also includes a diffusion barrier configured to substantiallyblock diffusion of glucose or hydrogen peroxide between the first andsecond working electrodes.

In a further embodiment, the glucose sensor includes a referenceelectrode configured integrally with the first and second workingelectrodes. In some embodiments, the reference electrode can be locatedremotely from the sensor, as described elsewhere herein. In someembodiments, the surface area of the reference electrode is at least sixtimes the surface area of the working electrodes. In some embodiments,the sensor includes a counter electrode that is integral to the sensoror is located remote from the sensor, as described elsewhere herein.

In a further embodiment, the glucose sensor detects a first signalassociated with glucose and non-glucose related electroactive compoundshaving a first oxidation potential (e.g., the oxidation potential ofH₂O₂). In some embodiments, the glucose sensor also detects a secondsignal is associated with background noise of the glucose sensorcomprising signal contribution due to interfering species,non-reaction-related hydrogen peroxide, or other electroactive specieswith an oxidation potential that substantially overlaps with theoxidation potential of hydrogen peroxide; the first and second workingelectrodes integrally form at least a portion of the sensor; and each ofthe first working electrode, the second working electrode and thenon-conductive material/insulator are configured provide at least twofunctions such as but not limited to electrical conductance, insulation,structural support, and a diffusion barrier

In further embodiments, the glucose sensor includes electronics operablyconnected to the first and second working electrodes. The electronicsare configured to calculate at least one analyte sensor data point usingthe first and second signals described above. In still another furtherembodiment, the electronics are operably connected to the first andsecond working electrode and are configured to process the first andsecond signals to generate a glucose concentration substantially withoutsignal contribution due to non-glucose noise artifacts.

Membrane Configurations

FIGS. 3A to 3B are cross-sectional exploded schematic views of thesensing region of a glucose sensor 10, which show architectures of themembrane system 22 disposed over electroactive surfaces of glucosesensors in some embodiments. In the illustrated embodiments of FIGS. 3Aand 3B, the membrane system 22 is positioned at least over theglucose-measuring working electrode 16 and the optional auxiliaryworking electrode 18; however the membrane system may be positioned overthe reference and/or counter electrodes 20, 22 in some embodiments.

Reference is now made to FIG. 3A, which is a cross-sectional explodedschematic view of the sensing region in one embodiment wherein an activeenzyme 32 of the enzyme domain is positioned only over theglucose-measuring working electrode 16. In this embodiment, the membranesystem is formed such that the glucose oxidase 32 only exists above theglucose-measuring working electrode 16. In one embodiment, during thepreparation of the membrane system 22, the enzyme domain coatingsolution can be applied as a circular region similar to the diameter ofthe glucose-measuring working electrode 16. This fabrication can beaccomplished in a variety of ways such as screen-printing or padprinting. Preferably, the enzyme domain is pad printed during the enzymedomain fabrication with equipment as available from Pad Print Machineryof Vermont (Manchester, VT). This embodiment provides the active enzyme32 above the glucose-measuring working electrode 16 only, so that theglucose-measuring working electrode 16 (and not the auxiliary workingelectrode 18) measures glucose concentration. Additionally, thisembodiment provides an added advantage of eliminating the consumption ofO₂ above the counter electrode (if applicable) by the oxidation ofglucose with glucose oxidase.

FIG. 3B is a cross-sectional exploded schematic view of a sensing regionof the preferred embodiments, and wherein the portion of the activeenzyme within the membrane system 22 positioned over the auxiliaryworking electrode 18 has been deactivated 34. In one alternativeembodiment, the enzyme of the membrane system 22 may be deactivated 34everywhere except for the area covering the glucose-measuring workingelectrode 16 or may be selectively deactivated only over certain areas(for example, auxiliary working electrode 18, counter electrode 22,and/or reference electrode 20) by irradiation, heat, proteolysis,solvent, or the like. In such a case, a mask (for example, such as thoseused for photolithography) can be placed above the membrane that coversthe glucose-measuring working electrode 16. In this way, exposure of themasked membrane to ultraviolet light deactivates the glucose oxidase inall regions except that covered by the mask.

In some alternative embodiments, the membrane system is disposed on thesurface of the electrode(s) using known deposition techniques. Theelectrode-exposed surfaces can be inset within the sensor body, planarwith the sensor body, or extending from the sensor body. Although someexamples of membrane systems have been provided above, the conceptsdescribed herein can be applied to numerous known architectures notdescribed herein.

Sensor Electronics

In some embodiments, the sensing region may include reference and/orelectrodes associated with the glucose-measuring working electrode andseparate reference and/or counter electrodes associated with theoptional auxiliary working electrode(s). In yet another embodiment, thesensing region may include a glucose-measuring working electrode, anauxiliary working electrode, two counter electrodes (one for eachworking electrode), and one shared reference electrode. In yet anotherembodiment, the sensing region may include a glucose-measuring workingelectrode, an auxiliary working electrode, two reference electrodes, andone shared counter electrode. However, a variety of electrode materialsand configurations can be used with the implantable analyte sensor ofthe preferred embodiments.

In some alternative embodiments, the working electrodes areinterdigitated. In some alternative embodiments, the working electrodeseach comprise multiple exposed electrode surfaces; one advantage ofthese architectures is to distribute the measurements across a greatersurface area to overcome localized problems that may occur in vivo, forexample, with the host's immune response at the biointerface.Preferably, the glucose-measuring and auxiliary working electrodes areprovided within the same local environment, such as described in moredetail elsewhere herein.

FIG. 4 is a block diagram that illustrates the continuous glucose sensorelectronics in one embodiment. In this embodiment, a first potentiostat36 is provided that is operatively associated with the glucose-measuringworking electrode 16. The first potentiostat 36 measures a current valueat the glucose-measuring working electrode and preferably includes aresistor (not shown) that translates the current into voltage. Anoptional second potentiostat 37 is provided that is operativelyassociated with the optional auxiliary working electrode 18. The secondpotentiostat 37 measures a current value at the auxiliary workingelectrode 18 and preferably includes a resistor (not shown) thattranslates the current into voltage. It is noted that in someembodiments, the optional auxiliary electrode can be configured to sharethe first potentiostat with the glucose-measuring working electrode. AnA/D converter 38 digitizes the analog signals from the potentiostats 36,37 into counts for processing. Accordingly, resulting raw data streams(in counts) can be provided that are directly related to the currentmeasured by each of the potentiostats 36 and 37.

A microprocessor 40, also referred to as the processor module, is thecentral control unit that houses EEPROM 42 and SRAM 44, and controls theprocessing of the sensor electronics. It is noted that certainalternative embodiments can utilize a computer system other than amicroprocessor to process data as described herein. In other alternativeembodiments, an application-specific integrated circuit (ASIC) can beused for some or all the sensor's central processing. The EEPROM 42provides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, such as described in U.S. Publication No. US-2005-0027463-A1,which is incorporated by reference herein in its entirety. The SRAM 44can be used for the system's cache memory, for example for temporarilystoring recent sensor data. In some alternative embodiments, memorystorage components comparable to EEPROM and SRAM may be used instead ofor in addition to the preferred hardware, such as dynamic RAM,non-static RAM, rewritable ROMs, flash memory, or the like.

A battery 46 is operably connected to the microprocessor 40 and providesthe necessary power for the sensor 10 a. In one embodiment, the batteryis a Lithium Manganese Dioxide battery, however any appropriately sizedand powered battery can be used (for example, AAA, Nickel-cadmium,Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride, Lithium-ion,Zinc-air, Zinc-mercury oxide, Silver-zinc, and/or hermetically-sealed).In some embodiments the battery is rechargeable. In some embodiments, aplurality of batteries can be used to power the system. In someembodiments, one or more capacitors can be used to power the system. AQuartz Crystal 48 may be operably connected to the microprocessor 40 tomaintain system time for the computer system as a whole.

An RF Transceiver 50 may be operably connected to the microprocessor 40to transmit the sensor data from the sensor 10 to a receiver (see FIGS.4 and 5 ) within a wireless transmission 52 via antenna 54. Although anRF transceiver is shown here, some other embodiments can include a wiredrather than wireless connection to the receiver. In yet otherembodiments, the receiver can be transcutaneously powered via aninductive coupling, for example. A second quartz crystal 56 can providethe system time for synchronizing the data transmissions from the RFtransceiver. It is noted that the transceiver 50 can be substituted witha transmitter in other embodiments. In some alternative embodimentsother mechanisms such as optical, infrared radiation (IR), ultrasonic,or the like may be used to transmit and/or receive data.

Receiver

FIG. 5 is a schematic drawing of a receiver for the continuous glucosesensor in one embodiment. The receiver 58 comprises systems necessary toreceive, process, and display sensor data from the analyte sensor, suchas described in more detail elsewhere herein. Particularly, the receiver58 may be a pager-sized device, for example, and house a user interfacethat has a plurality of buttons and/or keypad and a liquid crystaldisplay (LCD) screen, and which may include a backlight. In someembodiments the user interface may also include a speaker, and avibrator such as described with reference to FIG. 6 .

FIG. 6 is a block diagram of the receiver electronics in one embodiment.In some embodiments, the receiver comprises a configuration such asdescribed with reference to FIG. 5 , above. However, the receiver maycomprise any reasonable configuration, including a desktop computer,laptop computer, a personal digital assistant (PDA), a server (local orremote to the receiver), or the like. In some embodiments, a receivermay be adapted to connect (via wired or wireless connection) to adesktop computer, laptop computer, a PDA, a server (local or remote tothe receiver), or the like in order to download data from the receiver.In some alternative embodiments, the receiver may be housed within ordirectly connected to the sensor in a manner that allows sensor andreceiver electronics to work directly together and/or share dataprocessing resources. Accordingly, the receiver, including itselectronics, may be generally described as a “computer system.”

A quartz crystal 60 may be operably connected to an RF transceiver 62that together function to receive and synchronize data streams via anantenna 64 (for example, transmission 52 from the RF transceiver 50shown in FIG. 4 ). Once received, a microprocessor 66 can process thesignals, such as described below.

The microprocessor 66, also referred to as the processor module, is thecentral control unit that provides the processing, such as storing data,calibrating sensor data, downloading data, controlling the userinterface by providing prompts, messages, warnings and alarms, or thelike. The EEPROM 68 may be operably connected to the microprocessor 66and provides semi-permanent storage of data, storing data such asreceiver ID and programming to process data streams (for example,programming for performing calibration and other algorithms describedelsewhere herein). SRAM 70 may be used for the system's cache memory andis helpful in data processing. For example, the SRAM stores informationfrom the continuous glucose sensor for later recall by the patient or adoctor; a patient or doctor can transcribe the stored information at alater time to determine compliance with the medical regimen or acomparison of glucose concentration to medication administration (forexample, this can be accomplished by downloading the information throughthe pc com port 76). In addition, the SRAM 70 can also store updatedprogram instructions and/or patient specific information. In somealternative embodiments, memory storage components comparable to EEPROMand SRAM can be used instead of or in addition to the preferredhardware, such as dynamic RAM, non-static RAM, rewritable ROMs, flashmemory, or the like.

A battery 72 may be operably connected to the microprocessor 66 andprovides power for the receiver. In one embodiment, the battery is astandard AAA alkaline battery, however any appropriately sized andpowered battery can be used. In some embodiments, a plurality ofbatteries can be used to power the system. In some embodiments, a powerport (not shown) is provided permit recharging of rechargeablebatteries. A quartz crystal 84 may be operably connected to themicroprocessor 66 and maintains system time for the system as a whole.

A PC communication (com) port 76 can be provided to enable communicationwith systems, for example, a serial communications port, allows forcommunicating with another computer system (for example, PC, PDA,server, or the like). In one exemplary embodiment, the receiver is ableto download historical data to a physician's PC for retrospectiveanalysis by the physician. The PC communication port 76 can also be usedto interface with other medical devices, for example pacemakers,implanted analyte sensor patches, infusion devices, telemetry devices,or the like.

A user interface 78 comprises a keypad 80, speaker 82, vibrator 84,backlight 86, liquid crystal display (LCD) 88, and one or more buttons90. The components that comprise the user interface 78 provide controlsto interact with the user. The keypad 80 can allow, for example, inputof user information about himself/herself, such as mealtime, exercise,insulin administration, and reference glucose values. The speaker 82 canprovide, for example, audible signals or alerts for conditions such aspresent and/or predicted hyper- and hypoglycemic conditions. Thevibrator 84 can provide, for example, tactile signals or alerts forreasons such as described with reference to the speaker, above. Thebacklight 94 can be provided, for example, to aid the user in readingthe LCD in low light conditions. The LCD 88 can be provided, forexample, to provide the user with visual data output. In someembodiments, the LCD is a touch-activated screen. The buttons 90 canprovide for toggle, menu selection, option selection, mode selection,and reset, for example. In some alternative embodiments, a microphonecan be provided to allow for voice-activated control.

The user interface 78, which is operably connected to the microprocessor70, serves to provide data input and output for the continuous analytesensor. In some embodiments, prompts can be displayed to inform the userabout necessary maintenance procedures, such as “Calibrate Sensor” or“Replace Battery.” In some embodiments, prompts or messages can bedisplayed on the user interface to convey information to the user, suchas malfunction, outlier values, missed data transmissions, or the like.Additionally, prompts can be displayed to guide the user throughcalibration of the continuous glucose sensor, for example when to obtaina reference glucose value.

Keypad, buttons, touch-screen, and microphone are all examples ofmechanisms by which a user can input data directly into the receiver. Aserver, personal computer, personal digital assistant, insulin pump, andinsulin pen are examples of external devices that can be connected tothe receiver via PC com port 76 to provide useful information to thereceiver. Other devices internal or external to the sensor that measureother aspects of a patient's body (for example, temperature sensor,accelerometer, heart rate monitor, oxygen monitor, or the like) can beused to provide input helpful in data processing. In one embodiment, theuser interface can prompt the patient to select an activity most closelyrelated to their present activity, which can be helpful in linking to anindividual's physiological patterns, or other data processing. Inanother embodiment, a temperature sensor and/or heart rate monitor canprovide information helpful in linking activity, metabolism, and glucoseexcursions of an individual. While a few examples of data input havebeen provided here, a variety of information can be input and can behelpful in data processing as will be understood by one skilled in theart.

Calibration Systems and Methods

As described above in the Overview Section, continuous analyte sensorsdefine a relationship between sensor-generated measurements and areference measurement that is meaningful to a user (for example, bloodglucose in mg/dL). This defined relationship must be monitored to ensurethat the continuous analyte sensor maintains a substantially accuratecalibration and thereby continually provides meaningful values to auser. Unfortunately, both sensitivity m and baseline b of thecalibration are subject to changes that occur in vivo over time (forexample, hours to months), requiring updates to the calibration.Generally, any physical property that influences diffusion or transportof molecules through the membrane can alter the sensitivity (and/orbaseline) of the calibration. Physical properties that can alter thetransport of molecules include, but are not limited to, blockage ofsurface area due to foreign body giant cells and other barrier cells atthe biointerface, distance of capillaries from the membrane, foreignbody response/capsule, disease, tissue ingrowth, thickness of membranesystem, or the like.

In one example of a change in transport of molecules, an implantableglucose sensor is implanted in the subcutaneous space of a human, whichis at least partially covered with a biointerface membrane, such asdescribed in U.S. Publication No. US-2005-0112169-A1, which isincorporated by reference herein in its entirety. Although the body'snatural response to a foreign object is to encapsulate the sensor, thearchitecture of this biointerface membrane encourages tissue ingrowthand neo-vascularization over time, providing transport of solutes (forexample, glucose and oxygen) close to the membrane that covers theelectrodes. While not wishing to be bound by theory, it is believed thatingrowth of vascularized tissue matures (changes) over time, beginningwith a short period of high solute transport during the first few daysafter implantation, continuing through a time period of significanttissue ingrowth a few days to a week or more after implantation duringwhich low solute transport to the membrane has been observed, and into amature state of vascularized tissue during which the bed of vascularizedtissue provides moderate to high solute transport, which can last formonths and even longer after implantation. In some embodiments, thismaturation process accounts for a substantial portion of the change insensitivity and/or baseline of the calibration over time due to changesin solute transport to the membrane.

Accordingly, in one aspect of the preferred embodiments, systems andmethods are provided for measuring changes in sensitivity, also referredto as changes in solute transport or biointerface changes, of an analytesensor 10 implanted in a host over a time period. Preferably, thesensitivity measurement is a signal obtained by measuring a constantanalyte other than the analyte being measured by the analyte sensor. Forexample, in a glucose sensor, a non-glucose constant analyte ismeasured, wherein the signal is measured beneath the membrane system 22on the glucose sensor 10. While not wishing to be bound by theory, it isbelieved that by monitoring the sensitivity over a time period, a changeassociated with solute transport through the membrane system 22 can bemeasured and used as an indication of a sensitivity change in theanalyte measurement. In other words, a biointerface monitor is provided,which is capable of monitoring changes in the biointerface surroundingan implantable device, thereby enabling the measurement of sensitivitychanges of an analyte sensor over time.

In some embodiments, the analyte sensor 10 is provided with an auxiliaryelectrode 18 configured as a transport-measuring electrode disposedbeneath the membrane system 22. The transport-measuring electrode can beconfigured to measure any of a number of substantially constant analytesor factors, such that a change measured by the transport-measuringelectrode can be used to indicate a change in solute (for example,glucose) transport to the membrane system 22. Some examples ofsubstantially constant analytes or factors that can be measured include,but are not limited to, oxygen, carboxylic acids (such as urea), aminoacids, hydrogen, pH, chloride, baseline, or the like. Thus, thetransport-measuring electrode provides an independent measure of changesin solute transport to the membrane, and thus sensitivity changes overtime.

In some embodiments, the transport-measuring electrode measures analytessimilar to the analyte being measured by the analyte sensor. Forexample, in some embodiments of a glucose sensor, water soluble analytesare believed to better represent the changes in sensitivity to glucoseover time than non-water soluble analytes (due to the water-solubilityof glucose), however relevant information may be ascertained from avariety of molecules. Although some specific examples are describedherein, one skilled in the art appreciates a variety of implementationsof sensitivity measurements that can be used as to qualify or quantifysolute transport through the biointerface of the analyte sensor.

In one embodiment of a glucose sensor, the transport-measuring electrodeis configured to measure urea, which is a water-soluble constant analytethat is known to react directly or indirectly at a hydrogen peroxidesensing electrode (similar to the working electrode of the glucosesensor example described in more detail above). In one exemplaryimplementation wherein urea is directly measured by thetransport-measuring electrode, the glucose sensor comprises a membranesystem as described in more detail above, however, does not include anactive interference domain or active enzyme directly above thetransport-measuring electrode, thereby allowing the urea to pass throughthe membrane system to the electroactive surface for measurementthereon. In one alternative exemplary implementation wherein urea isindirectly measured by the transport-measuring electrode, the glucosesensor comprises a membrane system as described in more detail above,and further includes an active uricase oxidase domain located directlyabove the transport-measuring electrode, thereby allowing the urea toreact at the enzyme and produce hydrogen peroxide, which can be measuredat the electroactive surface thereon.

In some embodiments, the change in sensitivity is measured by measuringa change in oxygen concentration, which can be used to provide anindependent measurement of the maturation of the biointerface, and toindicate when recalibration of the system may be advantageous. In onealternative embodiment, oxygen is measured using pulsed amperometricdetection on the glucose-measuring working electrode 16 (eliminating theneed for a separate auxiliary electrode). In another embodiment, theauxiliary electrode is configured as an oxygen-measuring electrode. Inanother embodiment, an oxygen sensor (not shown) is added to the glucosesensor, as is appreciated by one skilled in the art, eliminating theneed for an auxiliary electrode.

In some embodiments, a stability module is provided; wherein thesensitivity measurement changes can be quantified such that a co-analyteconcentration threshold is determined. A co-analyte threshold isgenerally defined as a minimum amount of co-analyte required to fullyreact with the analyte in an enzyme-based analyte sensor in anon-limiting manner. The minimum co-analyte threshold is preferablyexpressed as a ratio (for example, a glucose-to-oxygen ratio) thatdefines a concentration of co-analyte required based on a concentrationof analyte available to ensure that the enzyme reaction is limited onlyby the analyte. While not wishing to be bound by theory, it is believedthat by determining a stability of the analyte sensor based on aco-analyte threshold, the processor module can be configured tocompensate for instabilities in the glucose sensor accordingly, forexample by filtering the unstable data, suspending calibration ordisplay, or the like.

In one such embodiment, a data stream from an analyte signal ismonitored and a co-analyte threshold set, whereby the co-analytethreshold is determined based on a signal-to-noise ratio exceeding apredetermined threshold. In one embodiment, the signal-to-noisethreshold is based on measurements of variability and the sensor signalover a time period, however one skilled in the art appreciates thevariety of systems and methods available for measuring signal-to-noiseratios. Accordingly, the stability module can be configured to setdetermine the stability of the analyte sensor based on the co-analytethreshold, or the like.

In some embodiments, the stability module is configured to prohibitcalibration of the sensor responsive to the stability (or instability)of the sensor. In some embodiments, the stability module can beconfigured to trigger filtering of the glucose signal responsive to astability (or instability) of the sensor.

In some embodiments, sensitivity changes can be used to trigger arequest for one or more new reference glucose values from the host,which can be used to recalibrate the sensor. In some embodiments, thesensor is re-calibrated responsive to a sensitivity change exceeding apreselected threshold value. In some embodiments, the sensor iscalibrated repeatedly at a frequency responsive to the measuredsensitivity change. Using these techniques, patient inconvenience can beminimized because reference glucose values are generally only requestedwhen timely and appropriate (namely, when a sensitivity or baselineshift is diagnosed).

In some alternative embodiments, sensitivity changes can be used toupdate calibration. For example, the measured change in transport can beused to update the sensitivity m in the calibration equation. While notwishing to be bound by theory, it is believed that in some embodiments,the sensitivity m of the calibration of the glucose sensor issubstantially proportional to the change in solute transport measured bythe transport-measuring electrode.

It should be appreciated by one skilled in the art that in someembodiments, the implementation of sensitivity measurements of thepreferred embodiments typically necessitate an addition to, ormodification of, the existing electronics (for example, potentiostatconfiguration or settings) of the glucose sensor and/or receiver.

In some embodiments, the signal from the oxygen measuring electrode maybe digitally low-pass filtered (for example, with a passband of 0-10-5Hz, dc-24 hour cycle lengths) to remove transient fluctuations inoxygen, due to local ischemia, postural effects, periods of apnea, orthe like. Since oxygen delivery to tissues is held in tight homeostaticcontrol, this filtered oxygen signal should oscillate about a relativelyconstant. In the interstitial fluid, it is thought that the levels areabout equivalent with venous blood (40 mmHg). Once implanted, changes inthe mean of the oxygen signal (for example, >5%) may be indicative ofchange in transport through the biointerface (change in sensorsensitivity and/or baseline due to changes in solute transport) and theneed for system recalibration.

The oxygen signal may also be used in its unfiltered or a minimallyfiltered form to detect or predict oxygen deprivation-induced artifactin the glucose signal, and to control display of data to the user, orthe method of smoothing, digital filtering, or otherwise replacement ofglucose signal artifact. In some embodiments, the oxygen sensor may beimplemented in conjunction with any signal artifact detection orprediction that may be performed on the counter electrode or workingelectrode voltage signals of the electrode system. U.S. Publication No.US-2005-0043598-A1, which is incorporated by reference in its entiretyherein, describes some methods of signal artifact detection andreplacement that may be useful such as described herein.

Preferably, the transport-measuring electrode is located within the samelocal environment as the electrode system associated with themeasurement of glucose, such that the transport properties at thetransport-measuring electrode are substantially similar to the transportproperties at the glucose-measuring electrode.

In a second aspect the preferred embodiments, systems and methods areprovided for measuring changes baseline, namely non-glucose relatedelectroactive compounds in the host. Preferably the auxiliary workingelectrode is configured to measure the baseline of the analyte sensorover time. In some embodiments, the glucose-measuring working electrode16 is a hydrogen peroxide sensor coupled to a membrane system 22containing an active enzyme 32 located above the electrode (such asdescribed in more detail with reference to FIGS. 1 to 4 , above). Insome embodiments, the auxiliary working electrode 18 is another hydrogenperoxide sensor that is configured similar to the glucose-measuringworking electrode however a portion 34 of the membrane system 22 abovethe base-measuring electrode does not have active enzyme therein, suchas described in more detail with reference to FIGS. 3A and 3B. Theauxiliary working electrode 18 provides a signal substantiallycomprising the baseline signal, b, which can be (for example,electronically or digitally) subtracted from the glucose signal obtainedfrom the glucose-measuring working electrode to obtain the signalcontribution due to glucose only according to the following equation:

Signal_(glucose only)=Signal_(glucose-measuring working electrode)−Signal_(baseline-measuring working electrode)

In some embodiments, electronic subtraction of the baseline signal fromthe glucose signal can be performed in the hardware of the sensor, forexample using a differential amplifier. In some alternative embodiments,digital subtraction of the baseline signal from the glucose signal canbe performed in the software or hardware of the sensor or an associatedreceiver, for example in the microprocessor.

One aspect the preferred embodiments provides for a simplifiedcalibration technique, wherein the variability of the baseline has beeneliminated (namely, subtracted). Namely, calibration of the resultantdifferential signal (Signal glucose only) can be performed with a singlematched data pair by solving the following equation:

y=mx

While not wishing to be bound by theory, it is believed that bycalibrating using this simplified technique, the sensor is made lessdependent on the range of values of the matched data pairs, which can besensitive to human error in manual blood glucose measurements, forexample. Additionally, by subtracting the baseline at the sensor (ratherthan solving for the baseline b as in conventional calibration schemes),accuracy of the sensor may increase by altering control of this variable(baseline b) from the user to the sensor. It is additionally believedthat variability introduced by sensor calibration may be reduced.

In some embodiments, the glucose-measuring working electrode 16 is ahydrogen peroxide sensor coupled to a membrane system 22 containing anactive enzyme 32 located above the electrode, such as described in moredetail above; however the baseline signal is not subtracted from theglucose signal for calibration of the sensor. Rather, multiple matcheddata pairs are obtained in order to calibrate the sensor (for exampleusing y=mx+b) in a conventional manner, and the auxiliary workingelectrode 18 is used as an indicator of baseline shifts in the sensorsignal. Namely, the auxiliary working electrode 18 is monitored forchanges above a certain threshold. When a significant change isdetected, the system can trigger a request (for example, from thepatient or caregiver) for a new reference glucose value (for example,SMBG), which can be used to recalibrate the sensor. By using theauxiliary working electrode signal as an indicator of baseline shifts,recalibration requiring user interaction (namely, new reference glucosevalues) can be minimized due to timeliness and appropriateness of therequests. In some embodiments, the sensor is re-calibrated responsive toa baseline shifts exceeding a preselected threshold value. In someembodiments, the sensor is calibrated repeatedly at a frequencyresponsive to the rate-of-change of the baseline.

In yet another alternative embodiment, the electrode system of thepreferred embodiments is employed as described above, includingdetermining the differential signal of glucose less baseline current inorder to calibrate using the simplified equation (y=mx), and theauxiliary working electrode 18 is further utilized as an indicator ofbaseline shifts in the sensor signal. While not wishing to be bound bytheory, it is believed that shifts in baseline may also correlate and/orbe related to changes in the sensitivity m of the glucose signal.Consequently, a shift in baseline may be indicative of a change insensitivity m. Therefore, the auxiliary working electrode 18 ismonitored for changes above a certain threshold. When a significantchange is detected, the system can trigger a request (for example, fromthe patient or caregiver) for a new reference glucose value (forexample, SMBG), which can be used to recalibrate the sensor. By usingthe auxiliary signal as an indicator of possible sensitivity changes,recalibration requiring user interaction (new reference glucose values)can be minimized due to timeliness and appropriateness of the requests.

It is noted that infrequent new matching data pairs may be useful overtime to recalibrate the sensor because the sensitivity m of the sensormay change over time (for example, due to maturation of the biointerfacethat may increase or decrease the glucose and/or oxygen availability tothe sensor). However, the baseline shifts that have conventionallyrequired numerous and/or regular blood glucose reference measurementsfor updating calibration (for example, due to interfering species,metabolism changes, or the like) can be consistently and accuratelyeliminated using the systems and methods of the preferred embodiments,allowing reduced interaction from the patient (for example, requestingless frequent reference glucose values such as daily or even asinfrequently as monthly).

An additional advantage of the sensor of the preferred embodimentsincludes providing a method of eliminating signal effects of interferingspecies, which have conventionally been problematic in electrochemicalglucose sensors. Namely, electrochemical sensors are subject toelectrochemical reaction not only with the hydrogen peroxide (or otheranalyte to be measured), but additionally may react with otherelectroactive species that are not intentionally being measured (forexample, interfering species), which cause an increase in signalstrength due to this interference. In other words, interfering speciesare compounds with an oxidation potential that overlap with the analytebeing measured. Interfering species such as acetaminophen, ascorbate,and urate, are notorious in the art of glucose sensors for producinginaccurate signal strength when they are not properly controlled. Someglucose sensors utilize a membrane system that blocks at least someinterfering species, such as ascorbate and urate. Unfortunately, it isdifficult to find membranes that are satisfactory or reliable in use,especially in vivo, which effectively block all interferants and/orinterfering species (for example, see U.S. Pat. Nos. 4,776,944,5,356,786, 5,593,852, 5,776,324B1, and U.S. Pat. No. 6,356,776).

The preferred embodiments are particularly advantageous in theirinherent ability to eliminate the erroneous transient and non-transientsignal effects normally caused by interfering species. For example, ifan interferant such as acetaminophen is ingested by a host implantedwith a conventional implantable electrochemical glucose sensor (namely,one without means for eliminating acetaminophen), a transientnon-glucose related increase in signal output would occur. However, byutilizing the electrode system of the preferred embodiments, bothworking electrodes respond with substantially equivalent increasedcurrent generation due to oxidation of the acetaminophen, which would beeliminated by subtraction of the auxiliary electrode signal from theglucose-measuring electrode signal.

In summary, the system and methods of the preferred embodiments simplifythe computation processes of calibration, decreases the susceptibilityintroduced by user error in calibration, and eliminates the effects ofinterfering species. Accordingly, the sensor requires less interactionby the patient (for example, less frequent calibration), increasespatient convenience (for example, few reference glucose values), andimproves accuracy (via simple and reliable calibration).

In another aspect of the preferred embodiments, the analyte sensor isconfigured to measure any combination of changes in baseline and/or insensitivity, simultaneously and/or iteratively, using any of theabove-described systems and methods. While not wishing to be bound bytheory, the preferred embodiments provide for improved calibration ofthe sensor, increased patient convenience through less frequent patientinteraction with the sensor, less dependence on the values/range of thepaired measurements, less sensitivity to error normally found in manualreference glucose measurements, adaptation to the maturation of thebiointerface over time, elimination of erroneous signal due tonon-constant analyte-related signal so interfering species, and/orself-diagnosis of the calibration for more intelligent recalibration ofthe sensor.

EXAMPLES Example 1: Dual-Electrode Sensor with Coiled ReferenceElectrode

Dual-electrode sensors (having a configuration similar to the embodimentshown in FIG. 9B) were constructed from two platinum wires, each coatedwith non-conductive material/insulator. Exposed electroactive windowswere cut into the wires by removing a portion thereof. The platinumwires were laid next to each other such that the windows are offset(e.g., separated by a diffusion barrier). The bundle was then placedinto a winding machine & silver wire was wrapped around the platinumelectrodes. The silver wire was then chloridized to produce asilver/silver chloride reference electrode. The sensor was trimmed tolength, and a glucose oxidase enzyme solution applied to both windows(e.g., enzyme applied to both sensors). To deactivate the enzyme in onewindow (e.g., window 904 a, FIG. 9B) the window was dipped intodimethylacetamide (DMAC) and rinsed. After the sensor was dried, aresistance layer was sprayed onto the sensor and dried.

FIG. 12 shows the results from one experiment, comparing the signalsfrom the two electrodes of the dual-electrode sensor having a coiledsilver/silver chloride wire reference electrode described above. The“Plus GOx” electrode included active GOx in its window. The “No GOx”electrode included DMAC-inactivated GOx in its window. To test, thesensor was incubated in room temperature phosphate buffered saline (PBS)for 30 minutes. During this time, the signals from the two electrodeswere substantially equivalent. Then the sensor was moved to a 40-mg/dlsolution of glucose in PBS. This increase in glucose concentrationresulting in an expected rise in signal from the “Plus GOx” electrodebut no significant increase in signal from the “No GOx” electrode. Thesensor was then moved to a 200-mg/dl solution of glucose in PBS. Again,the “Plus GOx” electrode responded with a characteristic signal increasewhile no increase in signal was observed for the “No GOx” electrode. Thesensor was then moved to a 400-mg/dl solution of glucose in PBS. The“Plus GOx” electrode signal increased to about 5000 counts while noincrease in signal was observed for the “No GOx” electrode. As a finaltest, the sensor was moved to a solution of 400 mg/dl glucose plus 0.22mM acetaminophen (a known interferant) in PBS. Both electrodes recordedsimilarly dramatic increases in signal (raw counts). These data indicatethat the “No GOx” electrode is measuring sensor background (e.g., noise)that is substantially related to non-glucose factors.

Example 2: Dual-Electrode Sensor with X-Shaped Reference Electrode

This sensor was constructed similarly to the sensor of Example 1, exceptthat the configuration was similar to the embodiment shown in FIG. 7J.Two platinum electrode wires were dipped into non-conductive materialand then electroactive windows formed by removing portions of thenonconductive material. The two wires were then bundled with an X-shapedsilver reference electrode therebetween. An additional layer ofnon-conductive material held the bundle together.

FIG. 13 shows the results from one experiment, comparing the signalsfrom the two electrodes of a dual-electrode sensor having an X-shapedreference electrode. The “Plus GOx” electrode has active GOx in itswindow. The “No GOx” electrode has DMAC-inactivated GOx in its window.The sensor was tested as was described for Experiment 1, above. Signalfrom the two electrodes were substantially equivalent until the sensorwas transferred to the 40-mg/dl glucose solution. As this point, the“Plus GOx” electrode signal increased but the “No GOx” electrode signaldid not. Similar increases were observed in the “Plus GOx” signal whenthe sensor was moved consecutively to 200-mg/dl and 400-mg/dl glucosesolution, but still not increase in the “No GOx” signal was observed.When sensor was moved to a 400-mg/dl glucose solution containing 0.22 mMacetaminophen, both electrodes recorded a similar increase in signal(raw counts). These data indicate that the “No GOx” electrode measuressensor background (e.g., noise) signal that is substantially related tonon-glucose factors.

Example 3: Dual-Electrode Challenge with Hydrogen Peroxide, Glucose, andAcetaminophen

A dual-electrode sensor was assembled similarly to the sensor of Example1, with a bundled configuration similar to that shown in FIG. 7C (twoplatinum working electrodes and one silver/silver chloride referenceelectrode, not twisted). The electroactive windows were staggered by0.085 inches, to create a diffusion barrier.

FIG. 14 shows the experimental results. The Y-axis shows the glucosesignal (volts) and the X-axis shows time. The “Enzyme” electrodeincluded active GOx. The “No Enzyme” electrode did not include activeGOx. The “Enzyme minus No Enzyme” represents a simple subtraction of the“Enzyme” minus the “NO Enzyme.” The “Enzyme” electrode measures theglucose-related signal and the non-glucose-related signal. The “NoEnzyme” electrode measures only the non-glucose-related signal. The“Enzyme minus No Enzyme” graph illustrates the portion of the “Enzyme”signal related to only the glucose-related signal.

The sensor was challenged with increasing concentrations of hydrogenperoxide in PBS. As expected, both the “Enzyme” and “No Enzyme”electrodes responded substantially the same with increases in signalcorresponding increased in H₂O₂ concentration (˜50 μM, 100 μM and 250 μMH₂O₂). When the “No Enzyme” signal was subtracted from the “Enzyme”signal, the graph indicated that the signal was not related to glucoseconcentration.

The sensor was challenged with increasing concentrations of glucose (˜20mg/dl, 200 mg/dl, 400 mg/dl) in PBS. As glucose concentration increased,the “Enzyme” electrode registered a corresponding increase in signal. Incontrast, the “No Enzyme” electrode did not record an increase insignal. Subtracting the “No Enzyme” signal from the “Enzyme” signalshows a step-wise increase in signal related to only glucoseconcentration.

The sensor was challenged with the addition of acetaminophen (˜0.22 mM)to the highest glucose concentration. Acetaminophen is known to be aninterferent (e.g., produces non-constant noise) of the sensors built asdescribed above, e.g., due to a lack of acetaminophen-blocking membraneand/or mechanism formed thereon or provided therewith. Both the “Enzyme”and “No Enzyme” electrodes showed a substantial increase in signal. The“Enzyme minus No Enzyme” graph substantially shows the portion of thesignal that was related to glucose concentration.

From these data, it is believed that a dual-electrode system can be usedto determine the analyte-only portion of the signal.

Example 4: IV Dual-Electrode Sensor in Dogs

An intravascular dual-electrode sensor was built substantially asdescribed in co-pending U.S. patent application Ser. No. 11/543,396filed on even date herewith and entitled “ANALYTE SENSOR.” Namely, thesensor was built by providing two platinum wires (e.g., dual workingelectrodes) and vapor-depositing the platinum wires with Parylene toform an insulating coating. A portion of the insulation on each wire wasremoved to expose the electroactive surfaces (e.g., 904 a and 904 b).The wires were bundled such that the windows were offset to provide adiffusion barrier, as described herein, cut to the desired length, toform an “assembly.” A silver/silver chloride reference electrode wasdisposed remotely from the working electrodes (e.g., coiled inside thesensor's fluid connector).

An electrode domain was formed over the electroactive surface areas ofthe working electrodes by dip coating the assembly in an electrodesolution (comprising BAYHYDROL® 123 with PVP and added EDC)) and drying.

An enzyme domain was formed over the electrode domain by subsequentlydip coating the assembly in an enzyme domain solution (BAYHYDROL 140AQmixed with glucose oxidase and glutaraldehyde) and drying. This dipcoating process was repeated once more to form an enzyme domain havingtwo layers and subsequently drying. Next an enzyme solution containingactive GOx was applied to one window; and an enzyme solution withoutenzyme (e.g., No GOx) was applied to the other window.

A resistance domain was formed over the enzyme domain by subsequentlyspray coating the assembly with a resistance domain solution(Chronothane H and Chronothane 1020) and drying.

After the sensor was constructed, it was placed in a protective sheathand then threaded through and attached to a fluid coupler, as describedin co-pending U.S. patent application Ser. No. 11/543,396 filed on evendate herewith and entitled “ANALYTE SENSOR.” Prior to use, the sensorswere sterilized using electron beam radiation.

The forelimb of an anesthetized dog (2 years old, ˜40 pounds) was cutdown to the femoral artery and vein. An arterio-venous shunt was placedfrom the femoral artery to the femoral vein using 14 gauge catheters and⅛-inch IV tubing. A pressurized arterial fluid line was connected to thesensor systems at all times. The test sensor system included a 20gauge×1.25-inch catheter and took measurements every 30 seconds. Thecatheter was aseptically inserted into the shunt, followed by insertionof the sensor into the catheter. As controls, the dog's glucose waschecked with an SMBG, as well as removing blood samples and measuringthe glucose concentration with a Hemocue.

FIG. 15 shows the experimental results. Glucose test data (counts) isshown on the left-hand Y-axis, glucose concentration for the controls(SMBG and Hemocue) are shown on the right-hand y-axis and time is shownon the X-axis. Each time interval on the X-axis represents 29-minutes(e.g., 12:11 to 12:40 equals 29 minutes). An acetaminophen challenge isshown as a vertical line on the graph.

The term “Plus GOx” refers to the signal from the electrode coated withactive GOx, which represents signal due to both the glucoseconcentration and non-glucose-related electroactive compounds asdescribed elsewhere herein (e.g., glucose signal and background signal,which includes both constant and non-constant noise). “No GOx” is signalfrom the electrode lacking GOx, which represents non-glucose relatedsignal (e.g., background signal, which includes both constant andnon-constant noise). The “Glucose Only” signal (e.g., related only toglucose concentration) is determined during data analysis (e.g., bysensor electronics). In this experiment, the “Glucose Only” signal wasdetermined by a subtraction of the “No GOx” signal from the “Plus GOx”signal.

During the experiment, the “No GOx” signal (thin line) substantiallyparalleled the “Plus GOx” signal (medium line). The “Glucose Only”signal substantially paralleled the control tests (SMBG/Hemocue).

Acetaminophen is known to be an interferent (e.g., produces non-constantnoise) of the sensors built as described above, e.g., due to a lack ofacetaminophen-blocking membrane and/or mechanism formed thereon orprovided therewith. The SMBG or Hemocue devices utilized in thisexperiment, however, do include mechanisms that substantially blockacetaminophen from the signal (see FIG. 15 ). When the dog waschallenged with acetaminophen, the signals from both working electrodes(“Plus GOx” and “No GOx”) increased in a substantially similar manner.When the “Glucose Only” signal was determined, it substantiallyparalleled the signals of the control devices and was of a substantiallysimilar magnitude.

From these experimental results, the inventors believe that anindwelling, dual-electrode glucose sensor system (as described herein)in contact with the circulatory system can provide substantiallycontinuous glucose data that can be used to calculate a glucoseconcentration that is free from background components (e.g., constantand non-constant noise), in a clinical setting.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. Nos.4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857; 6,558,321;6,931,327; 6,862,465; 7,074,307; 7,081,195; 7,108,778; and 7,110,803.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PublicationNo. US-2005-0176136-A1; U.S. Publication No. US-2005-0251083-A1; U.S.Publication No. US-2005-0143635-A1; U.S. Publication No.US-2005-0181012-A1; U.S. Publication No. US-2005-0177036-A1; U.S.Publication No. US-2005-0124873-A1; U.S. Publication No.US-2005-0115832-A1; U.S. Publication No. US-2005-0245799-A1; U.S.Publication No. US-2005-0245795-A1; U.S. Publication No.US-2005-0242479-A1; U.S. Publication No. US-2005-0182451-A1; U.S.Publication No. US-2005-0056552-A1; U.S. Publication No.US-2005-0192557-A1; U.S. Publication No. US-2005-0154271-A1; U.S.Publication No. US-2004-0199059-A1; U.S. Publication No.US-2005-0054909-A1; U.S. Publication No. US-2005-0112169-A1; U.S.Publication No. US-2005-0051427-A1; U.S. Publication No.US-2003-0032874-A1; U.S. Publication No. US-2005-0103625-A1; U.S.Publication No. US-2005-0203360-A1; U.S. Publication No.US-2005-0090607-A1; U.S. Publication No. US-2005-0187720-A1; U.S.Publication No. US-2005-0161346-A1; U.S. Publication No.US-2006-0015020-A1; U.S. Publication No. US-2005-0043598-A1; U.S.Publication No. US-2003-0217966-A1; U.S. Publication No.US-2005-0033132-A1; U.S. Publication No. US-2005-0031689-A1; U.S.Publication No. US-2004-0186362-A1; U.S. Publication No.US-2005-0027463-A1; U.S. Publication No. US-2005-0027181-A1; U.S.Publication No. US-2005-0027180-A1; U.S. Publication No.US-2006-0020187-A1; U.S. Publication No. US-2006-0036142-A1; U.S.Publication No. US-2006-0020192-A1; U.S. Publication No.US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-A1; U.S.Publication No. US-2006-0019327-A1; U.S. Publication No.US-2006-0020186-A1; U.S. Publication No. US-2006-0020189-A1; U.S.Publication No. US-2006-0036139-A1; U.S. Publication No.US-2006-0020191-A1; U.S. Publication No. US-2006-0020188-A1; U.S.Publication No. US-2006-0036141-A1; U.S. Publication No.US-2006-0020190-A1; U.S. Publication No. US-2006-0036145-A1; U.S.Publication No. US-2006-0036144-A1; U.S. Publication No.US-2006-0016700-A1; U.S. Publication No. US-2006-0142651-A1; U.S.Publication No. US-2006-0086624-A1; U.S. Publication No.US-2006-0068208-A1; U.S. Publication No. US-2006-0040402-A1; U.S.Publication No. US-2006-0036142-A1; U.S. Publication No.US-2006-0036141-A1; U.S. Publication No. US-2006-0036143-A1; U.S.Publication No. US-2006-0036140-A1; U.S. Publication No.US-2006-0036139-A1; U.S. Publication No. US-2006-0142651-A1; U.S.Publication No. US-2006-0036145-A1; U.S. Publication No.US-2006-0036144-A1; U.S. Publication No. US-2006-0200022-A1; U.S.Publication No. US-2006-0198864-A1; U.S. Publication No.US-2006-0200019-A1; U.S. Publication No. US-2006-0189856-A1; U.S.Publication No. US-2006-0200020-A1; U.S. Publication No.US-2006-0200970-A1; U.S. Publication No. US-2006-0183984-A1; U.S.Publication No. US-2006-0183985-A1; and U.S. Publication No.US-2006-0195029-A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/335,879filed Jan. 18, 2006 and entitled “CELLULOSIC-BASED INTERFERENCE DOMAINFOR AN ANALYTE SENSOR”; U.S. application Ser. No. 11/334,876 filed Jan.18, 2006 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. applicationSer. No. 11/498,410 filed Aug. 2, 2006 and entitled “SYSTEMS AND METHODSFOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”; U.S.application Ser. No. 11/515,443 filed Sep. 1, 2006 and entitled “SYSTEMSAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser.No. 11/503,367 filed Aug. 10, 2006 and entitled “ANALYTE SENSOR”; andU.S. application Ser. No. 11/515,342 filed Sep. 1, 2006 and entitled“SYSTEMS AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”.

All references cited herein are incorporated herein by reference intheir entireties. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.

What is claimed is:
 1. A method for measuring a sensitivity change of aglucose sensor implanted in a host over a time period, the methodcomprising: measuring a first signal in the host by obtaining at leastone glucose-related sensor data point, wherein the first signal ismeasured at a glucose-measuring electrode disposed beneath an enzymaticportion of a membrane system on the sensor; and measuring a secondsignal in the host by obtaining at least one non-glucose constant datapoint, wherein the second signal is measured beneath the membrane systemon the sensor; and monitoring the second signal over a time period,whereby a sensitivity change associated with solute transport throughthe membrane system is measured.
 2. The method of claim 1, wherein thesecond signal is indicative of a presence or absence of a water-solubleanalyte.
 3. The method of claim 2, wherein the water-soluble analytecomprises urea.
 4. The method of claim 1, wherein the second signal ismeasured at an oxygen-measuring electrode disposed beneath anon-enzymatic portion of the membrane system.
 5. The method of claim 1,wherein the glucose-measuring electrode incrementally measures oxygen,whereby the second signal is measured.
 6. The method of claim 1, whereinthe second signal is measured at an oxygen sensor disposed beneath themembrane system.
 7. The method of claim 1, wherein the sensitivitychange is calculated as a glucose-to-oxygen ratio, whereby an oxygenthreshold is determined that is indicative of a stability of the glucosesensor.
 8. The method of claim 7, further comprising filtering the firstsignal responsive to the stability of the glucose sensor.
 9. The methodof claim 7, further comprising displaying a glucose value derived fromthe first signal, wherein the display is suspended depending on thestability of the glucose sensor.
 10. The method of claim 7, furthercomprising calibrating the first signal, wherein the calibrating step issuspended when the glucose sensor is determined to be stable.
 11. Themethod of claim 1, further comprising calibrating the glucose sensorwhen the sensitivity change exceeds a preselected value.
 12. The methodof claim 11, wherein the step of calibrating comprises receiving areference signal from a reference analyte monitor, the reference signalcomprising at least one reference data point.
 13. The method of claim11, wherein the step of calibrating comprises using the sensitivitychange to calibrate the glucose sensor.
 14. The method of claim 11,wherein the step of calibrating is performed repeatedly at a frequencyresponsive to the sensitivity change.
 15. The method of claim 1, furthercomprising determining a stability of glucose transport through themembrane system, wherein the stability of glucose transport isdetermined by measuring the sensitivity change over a time period. 16.The method of claim 15, further comprising a step of prohibitingcalibration of the glucose sensor when glucose transport is determinedto be unstable.
 17. The method of claim 15, further comprising a step offiltering at least one glucose-related sensor data point when glucosetransport is determined to be unstable.
 18. A system for measuringglucose in a host, the system comprising: a glucose-measuring electrodeconfigured to generate a first signal comprising at least oneglucose-related sensor data point, wherein the glucose-measuringelectrode is disposed beneath an enzymatic portion of a membrane systemon a glucose sensor; and a transport-measuring electrode configured togenerate a second signal comprising at least one non-glucose constantanalyte data point, wherein the transport-measuring electrode issituated beneath the membrane system on the glucose sensor.
 19. Thesystem of claim 18, further comprising a processor module configured tomonitor the second signal whereby a sensitivity change associated withtransport of the non-glucose constant analyte through the membranesystem over a time period is measured.
 20. The system of claim 19,wherein the transport-measuring electrode is configured to measureoxygen.
 21. The system of claim 20, wherein the processor module isconfigured to determine whether a glucose-to-oxygen ratio exceeds athreshold level, wherein a value is calculated from the first signal andthe second signal, wherein the value is indicative of theglucose-to-oxygen ratio.
 22. The system of claim 19, wherein theprocessor module is configured to calibrate the glucose-related sensordata point in response to the sensitivity change.
 23. The system ofclaim 19, wherein the processor module is configured to receivereference data from a reference analyte monitor, the reference datacomprising at least one reference data point, wherein the processormodule is configured to use the reference data point for calibrating theglucose-related sensor data point.
 24. The system of claim 19, whereinthe processor module is configured to use the sensitivity change forcalibrating the glucose-related sensor data point.
 25. The system ofclaim 19, wherein the processor module is configured to calibrate theglucose-related sensor data point repeatedly at a frequency, wherein thefrequency is selected based on the sensitivity change.
 26. The system ofclaim 19, further comprising a stability module configured to determinea stability of glucose transport through the membrane system, whereinthe stability of glucose transport is correlated with the sensitivitychange.
 27. The system of claim 26, wherein the processor module isconfigured to prohibit calibration of the glucose-related sensor datapoint when the stability of glucose transport falls below a threshold.28. The system of claim 26, wherein the processor module is configuredto initiate filtering of the glucose-related sensor data point when thestability of glucose transport falls below a threshold.
 29. The systemof claim 19, wherein the transport-measuring electrode is configured tomeasure urea.
 30. A method for processing data from a glucose sensor ina host, the method comprising: measuring a first signal associated withglucose and non-glucose related electroactive compounds, wherein thefirst signal is measured at a first electrode disposed beneath an activeenzymatic portion of a membrane system; measuring a second signalassociated with a non-glucose related electroactive compound, whereinthe second signal is measured at a second electrode that is disposedbeneath a non-enzymatic portion of the membrane system; and monitoringthe second signal over a time period, whereby a change in thenon-glucose related electroactive compound in the host is measured. 31.The method of claim 30, further comprising a step of subtracting thesecond signal from the first signal, whereby a differential signalcomprising at least one glucose sensor data point is determined.
 32. Themethod of claim 31, wherein the step of subtracting is performedelectronically in the sensor.
 33. The method of claim 31, wherein thestep of subtracting is performed digitally in the sensor or anassociated receiver.
 34. The method of claim 31, further comprisingcalibrating the glucose sensor, wherein the step of calibratingcomprises: receiving reference data from a reference analyte monitor,the reference data comprising at least two reference data points;providing at least two matched data pairs by matching the reference datato substantially time corresponding sensor data; and calibrating theglucose sensor using the two or more matched data pairs and thedifferential signal.
 35. The method of claim 30, further comprising astep of calibrating the glucose sensor in response to a change in anon-glucose related electroactive compound over the time period.
 36. Themethod of claim 35, wherein the step of calibrating comprises receivingreference data from a reference analyte monitor, the reference datacomprising at least one reference data point.
 37. The method of claim35, wherein the step of calibrating comprises using the change in thenon-glucose related electroactive compound over the time period tocalibrate the glucose sensor.
 38. The method of claim 35, wherein thestep of calibrating is performed repeatedly at a frequency, wherein thefrequency is selected based on the change in the non-glucose relatedelectroactive compound over the time period.
 39. The method of claim 30,further comprising prohibiting calibration of the glucose sensor whenthe change in the non-glucose related electroactive compound rises abovea threshold during the time period.
 40. The method of claim 31, furthercomprising filtering the glucose sensor data point when the change inthe non-glucose related electroactive compound rises above a thresholdduring the time period.
 41. The method of claim 31, further comprisingmeasuring a third signal in the host by obtaining at least onenon-glucose constant data point, wherein the third signal is measuredbeneath the membrane system.
 42. The method of claim 41, furthercomprising monitoring the third signal over a time period, whereby asensitivity change associated with solute transport through the membranesystem is measured.
 43. The method of claim 41, wherein anoxygen-measuring electrode disposed beneath the non-enzymatic portion ofthe membrane system measures the third signal.
 44. The method of claim41, wherein the first electrode measures the third signal byincrementally measuring oxygen.
 45. The method of claim 41, wherein anoxygen sensor disposed beneath the membrane system measures the thirdsignal.
 46. The method of claim 41, wherein an urea-measuring electrodedisposed beneath the non-enzymatic portion of the membrane systemmeasures the third signal.
 47. The method of claim 41, wherein the firstelectrode measures the third signal by incrementally measuring urea. 48.The method of claim 41, wherein an urea sensor disposed beneath themembrane system measures the third signal.
 49. The method of claim 30,further comprising determining whether a glucose-to-oxygen ratio exceedsa threshold level by calculating a value from the first signal and thesecond signal, wherein the value is indicative of the glucose-to-oxygenratio.
 50. The method of claim 42, further comprising calibrating theglucose sensor in response to the sensitivity change measured over atime period.
 51. The method of claim 49, wherein the step of calibratingcomprises receiving reference data from a reference analyte monitor, thereference data comprising at least one reference data point.
 52. Themethod of claim 49, wherein the step of calibrating comprises using thesensitivity change.
 53. The method of claim 49, wherein the step ofcalibrating is performed repeatedly at a frequency, wherein thefrequency is selected based on the sensitivity change.
 54. The method ofclaim 42, further comprising determining glucose transport stabilitythrough the membrane system, wherein the glucose transport stabilitycorresponds to the sensitivity change over a period of time.
 55. Themethod of claim 54, further comprising prohibiting calibration of theglucose sensor when the glucose transport stability falls below athreshold.
 56. The method of claim 54, further comprising filtering theglucose-related sensor data point when the glucose transport stabilityfalls below a threshold.
 57. A system for measuring glucose in a host,the system comprising: a first working electrode configured to generatea first signal associated with a glucose related electroactive compoundand a non-glucose related electroactive compound, wherein the firstelectrode is disposed beneath an active enzymatic portion of a membranesystem on a glucose sensor; a second working electrode configured togenerate a second signal associated with the non-glucose relatedelectroactive compound, wherein the second electrode is disposed beneatha non-enzymatic portion of the membrane system on the glucose sensor;and a processor module configured to monitor the second signal over atime period, whereby a change in the non-glucose related electroactivecompound is measured.
 58. The system of claim 57, further comprising asubtraction module configured to subtract the second signal from thefirst signal, whereby a differential signal comprising at least oneglucose sensor data point is determined.
 59. The system of claim 58,wherein the subtraction module comprises a differential amplifierconfigured to electronically subtract the second signal from the firstsignal.
 60. The system of claim 57, wherein the subtraction modulecomprises at least one of hardware and software configured to digitallysubtract the second signal from the first signal.
 61. The system ofclaim 57, further comprising a reference electrode, wherein the firstworking electrode and the second working electrode are operativelyassociated with the reference electrode.
 62. The system of claim 61,further comprising a counter electrode, wherein the first workingelectrode and the second working electrode are operatively associatedwith the counter electrode.
 63. The system of claim 57, furthercomprising a first reference electrode and a second reference electrode,wherein the first reference electrode is operatively associated with thefirst working electrode, and wherein the second reference electrode isoperatively associated with the second working electrode.
 64. The systemof claim 63, further comprising a first counter electrode and a secondcounter electrode, wherein the first counter electrode is operativelyassociated with the first working electrode, and wherein the secondcounter electrode is operatively associated with the second workingelectrode.
 65. The system of claim 58, further comprising a referenceinput module adapted to obtain reference data from a reference analytemonitor, the reference data comprising at least one reference datapoint, wherein the processor module is configured to format at least onematched data pair by matching the reference data to substantially timecorresponding glucose sensor data and subsequently calibrating thesystem using at least two matched data pairs and the differentialsignal.
 66. The system of claim 58, wherein the processor module isconfigured to calibrate the system in response to the change in thenon-glucose related electroactive compound in the host over the timeperiod.
 67. The system of claim 66, wherein the processor module isconfigured to request reference data from a reference analyte monitor,the reference data comprising at least one reference data point, whereinthe processor module is configured to recalibrate the system using thereference data.
 68. The system of claim 66, wherein the processor moduleis configured to recalibrate the system using the change in thenon-glucose related electroactive compound measured over the timeperiod.
 69. The system of claim 66, wherein the processor module isconfigured to repeatedly recalibrate at a frequency, wherein thefrequency is selected based on the change in the non-glucose relatedelectroactive compound over the time period.
 70. The system of claim 65,wherein the processor module is configured to prohibit calibration ofthe system when a change in the non-glucose related electroactivecompound rises above a threshold during the time period.
 71. The systemof claim 58, wherein the processor module is configured to filter theglucose sensor data point when the change in the non-glucose relatedelectroactive compound rises above a threshold during the time period.72. The system of claim 58, further comprising a third electrodeconfigured to generate a third signal, the third signal comprising atleast one non-glucose constant analyte data point, wherein the thirdelectrode is disposed beneath the membrane system on the sensor.
 73. Thesystem of claim 72, wherein the third electrode is configured to measureoxygen.
 74. The system of claim 72, wherein the processor module isconfigured to determine whether a glucose-to-oxygen ratio exceeds athreshold level, wherein a value indicative of the glucose-to-oxygenratio is calculated from the first signal and the second signal.
 75. Thesystem of claim 72, wherein the processor module is configured tomonitor the third signal over a time period, whereby a sensitivitychange associated with solute transport through the membrane system ismeasured.
 76. The system of claim 75, wherein the processor module isconfigured to calibrate the glucose-related sensor data point inresponse to the sensitivity change.
 77. The system of claim 72, whereinthe processor module is configured to receive reference data from areference analyte monitor, the reference data comprising at least onereference data point, wherein the processor module is configured tocalibrate the glucose sensor data point using the reference data point.78. The system of claim 75, wherein the processor module is configuredto calibrate the glucose-related sensor data point repeatedly at afrequency, wherein the frequency is selected based on the sensitivitychange.
 79. The system of claim 75, further comprising a stabilitymodule configured to determine a stability of glucose transport throughthe membrane system, wherein the stability of glucose transport iscorrelated with the sensitivity change.
 80. The system of claim 78,wherein the processor module is configured to prohibit calibration ofthe glucose-related sensor data point when the stability of glucosetransport falls below a threshold.
 81. The system of claim 78, whereinthe processor module is configured to filter the glucose-related sensordata point when the stability of glucose transport falls below athreshold.
 82. The system of claim 72, wherein the third electrode isconfigured to measure urea.